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Allele associated with poor outcome in CLL
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom. 
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom.
A form of the CYP3A7 gene is associated with poor outcomes in chronic lymphocytic leukemia (CLL) and other cancers, according to a study published in Cancer Research.
Among patients with CLL, breast cancer, or lung cancer, those with the CYP3A7*1C allele were more likely than those without it to experience disease progression or death.
Researchers believe this may be related to how patients metabolize treatment.
“The CYP3A7 gene encodes an enzyme that breaks down all sorts of naturally occurring substances—such as sex steroids like estrogen and testosterone—as well as a wide range of drugs that are used in the treatment of cancer,” said Olivia Fletcher, PhD, of The Institute of Cancer Research in London, UK.
“The CYP3A7 gene is normally turned on in an embryo and then turned off shortly after a baby is born, but individuals who have 1 or more copies of the CYP3A7*1C form of the gene turn on their CYP3A7 gene in adult life.”
“We found that individuals with breast cancer, lung cancer, or CLL who carry 1 or more copies of the CYP3A7*1C allele tend to have worse outcomes. One possibility is that these patients break down the drugs that they are given to treat their cancer too fast. However, further independent studies that replicate our findings in larger numbers of patients and rule out biases are needed before we could recommend any changes to the treatment that cancer patients with the CYP3A7*1C allele receive.”
To assess the impact of the CYP3A7*1C allele on patient outcomes, Dr Fletcher and her colleagues analyzed DNA samples from 1008 breast cancer patients, 1142 patients with lung cancer, and 356 patients with CLL.
The team looked for the presence of the single nucleotide polymorphism (SNP) rs45446698. Dr Fletcher explained that rs45446698 is 1 of 7 SNPs that cluster together to form the CYP3A7*1C allele.
The researchers found that, among CLL patients, rs45446698 (and, therefore, the CYP3A7*1C allele) was associated with a 62% increased risk of disease progression (P=0.03).
Among breast cancer patients, rs45446698 was associated with a 74% increased risk of breast cancer mortality (P=0.03). And among the lung cancer patients, the SNP was associated with a 43% increased risk of death from any cause (P=0.009).
The researchers also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P=0.06).
“Even though we did not see a statistically significant difference when stratifying patients by treatment with a CYP3A7 substrate, the fact that we see the same effect in 3 very different cancer types suggests to me that it is more likely to be something to do with treatment than the disease itself,” Dr Fletcher said.
“However, we are looking at ways of replicating these results in additional cohorts of patients and types of cancer, as well as overcoming the limitations of this study.”
Dr Fletcher explained that the main limitation of this study is that the researchers used samples and clinical information collected for other studies. So they did not have the same clinical information for each patient, and the samples were collected at different time points and for patients treated with various drugs.
She also noted that the researchers were not able to determine how quickly the patients broke down their treatments.
This study was supported by Sanofi-Aventis, Breast Cancer Now, Bloodwise, Cancer Research UK, the Medical Research Council, the Cridlan Trust, and the Helen Rollason Cancer Charity. The authors’ institutions received funding from the National Health Service of the United Kingdom.
Study elucidates MYC’s role in T-ALL
Image by Juha Klefstrom
Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.
Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.
The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).
The study was published in Science.
“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.
Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.
In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.
“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.
So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.
The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.
In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.
In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.
The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.
The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.
Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.
These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.
“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.
Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.
“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”
Image by Juha Klefstrom
Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.
Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.
The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).
The study was published in Science.
“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.
Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.
In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.
“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.
So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.
The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.
In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.
In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.
The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.
The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.
Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.
These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.
“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.
Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.
“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”
Image by Juha Klefstrom
Research has revealed a relationship between the oncogene MYC and 2 cell-surface proteins that protect cancer cells from the immune system—CD47 and PD-L1.
Researchers discovered that MYC regulates the expression of CD47 and PD-L1 in T-cell acute lymphoblastic leukemia (T-ALL) and several solid tumor malignancies.
The team said this study is the first to link 2 critical steps in cancer development—uncontrolled cell growth (courtesy of mutated or misregulated MYC) and an ability to “outsmart” the immune molecules meant to stop it (via CD47 and PD-L1).
The study was published in Science.
“Our findings describe an intimate, causal connection between how oncogenes like MYC cause cancer and how those cancer cells manage to evade the immune system,” said study author Dean Felsher, MD, PhD, of the Stanford University School of Medicine in California.
Researchers in Dr Felsher’s lab have been studying MYC for more than a decade, focusing on oncogene addiction, in which tumor cells are completely dependent on the expression of the oncogene. Blocking the expression of MYC in these cases causes the complete regression of tumors in animals.
In 2010, Dr Felsher and his colleagues showed this regression could only occur in animals with an intact immune system, but it wasn’t clear why.
“Since then, I’ve had it in the back of my mind that there must be a relationship between MYC and the immune system,” Dr Felsher said.
So he and his colleagues decided to see if there was a link between MYC expression and the levels of CD47 and PD-L1 proteins on the surface of cancer cells. They investigated what would happen if they actively turned off MYC expression in tumor cells from mice or humans.
The researchers found that a reduction in MYC caused a similar reduction in the levels of CD47 and PD-L1 proteins on the surface of mouse and human T-ALL cells, mouse and human liver cancer cells, human skin cancer cells, and human non-small-cell lung cancer cells.
In contrast, levels of other immune regulatory molecules found on the surface of the cells were unaffected.
In gene expression data on tumor samples from hundreds of patients, the researchers found that levels of MYC expression correlated strongly with expression levels of CD47 and PD-L1 genes in liver, kidney, and colorectal tumors.
The team then looked directly at the regulatory regions in the CD47 and PD-L1 genes. They found high levels of the MYC protein bound directly to the promoter regions of CD47 and PD-L1 in mouse T-ALL cells and in a human osteosarcoma cell line.
The researchers were also able to verify that this binding increased the expression of CD47 in a human B cell line.
Finally, the team engineered mouse T-ALL cells to constantly express CD47 or PD-L1 regardless of MYC expression status.
These cells were better able than control cells to evade the detection of immune cells like macrophages and T cells. And, unlike in previous experiments, tumors arising from these cells did not regress when MYC expression was deactivated.
“What we’re learning is that if CD47 and PD-L1 are present on the surfaces of cancer cells, even if you shut down a cancer gene, the animal doesn’t mount an adequate immune response, and the tumors don’t regress,” Dr Felsher said.
Therefore, this work suggests a combination of therapies targeting the expression of both MYC and CD47 or PD-L1 could possibly have a synergistic effect by slowing or stopping tumor growth and waving a red flag at the immune system.
“There is a growing sense of tremendous excitement in the field of cancer immunotherapy,” Dr Felsher said. “In many cases, it’s working, but it’s not been clear why some cancers are more sensitive than others. Our work highlights a direct link between oncogene expression and immune regulation that could be exploited to help patients.”
Germline mutations linked to hematologic malignancies
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
A new study suggests mutations in the gene DDX41 occur in families where hematologic malignancies are common.
Previous research showed that both germline and acquired DDX41 mutations occur in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
The new study, published in Blood, has linked germline mutations in DDX41 to chronic myeloid leukemia and lymphomas as well.
“This is the first gene identified in families with lymphoma and represents a major breakthrough for the field,” said study author Hamish Scott, PhD, of the University of Adelaide in South Australia.
“Researchers are recognizing now that genetic predisposition to blood cancer is more common than previously thought, and our study shows the importance of taking a thorough family history at diagnosis.”
To conduct this study, Dr Scott and his colleagues screened 2 cohorts of families with a range of hematologic disorders (malignant and non-malignant). One cohort included 240 individuals from 93 families in Australia. The other included 246 individuals from 198 families in the US.
In all, 9 of the families (3%) had germline DDX41 mutations.
Three families carried the recurrent p.D140Gfs*2 mutation, which was linked to AML.
One family carried a germline mutation—p.R525H, c.1574G.A—that was previously described only as a somatic mutation at the time of progression to MDS or AML. In the current study, the mutation was again linked to MDS and AML.
Five families carried novel DDX41 mutations.
One of these mutations was a germline substitution—c.435-2_435-1delAGinsCA—that was linked to MDS in 1 family.
Two families had a missense start-loss substitution—c.3G.A, p.M1I—that was linked to MDS, AML, chronic myeloid leukemia, and non-Hodgkin lymphoma.
One family had a DDX41 missense variant—c.490C.T, p.R164W. This was linked to Hodgkin and non-Hodgkin lymphoma (including 3 cases of follicular lymphoma). There was a possible link to multiple myeloma as well, but the diagnosis could not be confirmed.
And 1 family had a missense mutation in the helicase domain—p.G530D—that was linked to AML.
“DDX41 is a new type of cancer predisposition gene, and we are still investigating its function,” Dr Scott noted.
“But it appears to have dual roles in regulating the correct expression of genes in the cell and also enabling the immune system to respond to threats such as bacteria and viruses, as well as the development of cancer cells. Immunotherapy is a promising approach for cancer treatment, and our research to understand the function of DDX41 will help design better therapies.”
Compound could treat T-ALL subtype
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
Photo courtesy of
The Ottawa Hospital
An experimental compound is “highly promising” as a potential treatment for a subtype of T-cell acute lymphoblastic leukemia (T-ALL), according to researchers.
The team found the histone demethylase UTX is important for the maintenance of TAL1-positive T-ALL.
Inhibiting UTX with a compound known as GSK-J4 proved toxic to TAL1-positive T-ALL cells in vitro and in vivo, but normal cells were spared.
The researchers reported these findings in Genes & Development.
“It’s very exciting because this is the first time anyone has found a potential personalized treatment for this aggressive disease,” said study author Marjorie Brand, PhD, of The Ottawa Hospital Research Institute in Ontario, Canada.
“Unlike current therapies, ours targets the offending gene without harming the rest of the body.”
Dr Brand and her colleagues decided the best way to find a better treatment for TAL1-positive T-ALL was to investigate exactly how it works at a molecular level. So they analyzed the TAL1 gene, which, in certain circumstances, can transform T-cell precursors into leukemic cells.
They found that TAL1 needs UTX to trigger leukemia production. This was surprising because UTX was previously described as a tumor suppressor in T-ALL.
The team said their work suggests UTX is actually a pro-oncogenic cofactor that is essential for leukemia maintenance in TAL1-positive—but not TAL1-negative—T-ALL.
The researchers found that targeting UTX with the H3K27 demethylase inhibitor GSK-J4 could completely halt the growth of TAL1-positive leukemia cells and induce apoptosis in these cells in vitro. But the compound did not have the same effect in TAL1-negative T-ALL.
The team also tested GSK-J4 in mouse models of T-ALL. After 3 weeks of treatment, there was a “dramatic decrease” in the percentage of leukemic blasts in the bone marrow of mice with TAL1-positive T-ALL. These mice also had a reduction in the infiltration of leukemic cells in the spleen.
However, mice with TAL1-negative T-ALL did not experience the same benefits.
The researchers said GSK-J4 appeared to be well-tolerated. None of the treated mice experienced weight loss or adverse effects in the intestine, spleen, liver, kidney, or hematopoietic system.
“While our study is a proof-of-concept, these promising results might one day lead to a similar targeted treatment for humans,” said study author Carmen Palii, PhD, also of The Ottawa Hospital Research Institute.
In the meantime, the researchers are conducting additional studies in mice, testing higher doses of GSK-J4 and evaluating long-term side effects of the compound.
Children who have stem cell transplants need skin exams, sun protection
WASHINGTON – Children who have had a hematopoietic stem cell transplant (HSCT) have an increased risk of benign and atypical nevi, Dr. Johanna Sheu reported at the annual meeting of the American Academy of Dermatology.
These patients need to have routine skin exams and be educated about sun protection needs, she said. Based on her study, these needs are not routinely met.
At least 1 year after undergoing HSCT at Boston Children’s Hospital, 85 posttransplant patients had significantly more nevi and more atypical nevi than did 85 healthy controls who were matched by age, gender, and Fitzpatrick skin type. In addition, 41% of the transplant recipients had at least one actinic keratosis, a basal or squamous cell carcinoma, or a solar lentigo; 11% had at least one nevus spilus.
Moreover, “sun protection … and dermatology follow-up was poor” among the transplant recipients, said Dr. Sheu, of MassGeneral Hospital for Children, Boston. About 40% of the transplant recipients reported having a sunburn since their transplant, only 15% reported daily use of sunscreen, and 53% said they did not recall being told that sunburn could trigger graft-versus-host disease (GVHD).
About one-third of the patients had never seen a dermatologist; of those who had, two-thirds had only seen the dermatologist once, Dr. Sheu reported.
Late skin effects of HSCT are not as well described in children as they are in adults, she said. In adults, late skin effects include vitiligo, psoriasis, nonmelanoma skin cancers, and an increased nevi count.
The children in the study had undergone an HSCT between 1998 and 2013, at a median age of about 7 years (range was 1 month to 19 years). At the time of their skin exams, their mean age was 14 years, and they had been followed for a median of almost 4 years. Nevi were counted on the forearms, backs, legs, palms, and soles.
The median nevi count was 44 nevi, significantly more than the level seen in control subjects. Transplant recipients also had significantly more nevi in sun-exposed areas of the body, as well as on the palms and soles. Transplant recipients were more likely to have atypical nevi and to have nevi greater than 5 mm in diameter.
In addition to fair skin, factors associated with an increase in the overall nevi count included being older than age 10 at the time of the transplant and having total body irradiation, pretransplant chemotherapy, and myeloablative conditioning. Having had a sunburn since the transplant, reported by 40%, was also a risk factor.
Chronic GVHD and chronic GVHD of the skin were associated with the presence of atypical nevi; acute GVHD, the duration of immune suppression, and the use of topical steroids or calcineurin inhibitors were not associated with increased risk of atypical nevi.
She and her coinvestigators are currently analyzing the pathogenesis of these late effects in this population, and autoimmune skin conditions – vitiligo and alopecia – in 25% of the transplant recipients in the study.
In 2013, 1,100 children under aged 16 years in the United States underwent a bone marrow transplant, she noted.
Dr. Sheu had no disclosures.
WASHINGTON – Children who have had a hematopoietic stem cell transplant (HSCT) have an increased risk of benign and atypical nevi, Dr. Johanna Sheu reported at the annual meeting of the American Academy of Dermatology.
These patients need to have routine skin exams and be educated about sun protection needs, she said. Based on her study, these needs are not routinely met.
At least 1 year after undergoing HSCT at Boston Children’s Hospital, 85 posttransplant patients had significantly more nevi and more atypical nevi than did 85 healthy controls who were matched by age, gender, and Fitzpatrick skin type. In addition, 41% of the transplant recipients had at least one actinic keratosis, a basal or squamous cell carcinoma, or a solar lentigo; 11% had at least one nevus spilus.
Moreover, “sun protection … and dermatology follow-up was poor” among the transplant recipients, said Dr. Sheu, of MassGeneral Hospital for Children, Boston. About 40% of the transplant recipients reported having a sunburn since their transplant, only 15% reported daily use of sunscreen, and 53% said they did not recall being told that sunburn could trigger graft-versus-host disease (GVHD).
About one-third of the patients had never seen a dermatologist; of those who had, two-thirds had only seen the dermatologist once, Dr. Sheu reported.
Late skin effects of HSCT are not as well described in children as they are in adults, she said. In adults, late skin effects include vitiligo, psoriasis, nonmelanoma skin cancers, and an increased nevi count.
The children in the study had undergone an HSCT between 1998 and 2013, at a median age of about 7 years (range was 1 month to 19 years). At the time of their skin exams, their mean age was 14 years, and they had been followed for a median of almost 4 years. Nevi were counted on the forearms, backs, legs, palms, and soles.
The median nevi count was 44 nevi, significantly more than the level seen in control subjects. Transplant recipients also had significantly more nevi in sun-exposed areas of the body, as well as on the palms and soles. Transplant recipients were more likely to have atypical nevi and to have nevi greater than 5 mm in diameter.
In addition to fair skin, factors associated with an increase in the overall nevi count included being older than age 10 at the time of the transplant and having total body irradiation, pretransplant chemotherapy, and myeloablative conditioning. Having had a sunburn since the transplant, reported by 40%, was also a risk factor.
Chronic GVHD and chronic GVHD of the skin were associated with the presence of atypical nevi; acute GVHD, the duration of immune suppression, and the use of topical steroids or calcineurin inhibitors were not associated with increased risk of atypical nevi.
She and her coinvestigators are currently analyzing the pathogenesis of these late effects in this population, and autoimmune skin conditions – vitiligo and alopecia – in 25% of the transplant recipients in the study.
In 2013, 1,100 children under aged 16 years in the United States underwent a bone marrow transplant, she noted.
Dr. Sheu had no disclosures.
WASHINGTON – Children who have had a hematopoietic stem cell transplant (HSCT) have an increased risk of benign and atypical nevi, Dr. Johanna Sheu reported at the annual meeting of the American Academy of Dermatology.
These patients need to have routine skin exams and be educated about sun protection needs, she said. Based on her study, these needs are not routinely met.
At least 1 year after undergoing HSCT at Boston Children’s Hospital, 85 posttransplant patients had significantly more nevi and more atypical nevi than did 85 healthy controls who were matched by age, gender, and Fitzpatrick skin type. In addition, 41% of the transplant recipients had at least one actinic keratosis, a basal or squamous cell carcinoma, or a solar lentigo; 11% had at least one nevus spilus.
Moreover, “sun protection … and dermatology follow-up was poor” among the transplant recipients, said Dr. Sheu, of MassGeneral Hospital for Children, Boston. About 40% of the transplant recipients reported having a sunburn since their transplant, only 15% reported daily use of sunscreen, and 53% said they did not recall being told that sunburn could trigger graft-versus-host disease (GVHD).
About one-third of the patients had never seen a dermatologist; of those who had, two-thirds had only seen the dermatologist once, Dr. Sheu reported.
Late skin effects of HSCT are not as well described in children as they are in adults, she said. In adults, late skin effects include vitiligo, psoriasis, nonmelanoma skin cancers, and an increased nevi count.
The children in the study had undergone an HSCT between 1998 and 2013, at a median age of about 7 years (range was 1 month to 19 years). At the time of their skin exams, their mean age was 14 years, and they had been followed for a median of almost 4 years. Nevi were counted on the forearms, backs, legs, palms, and soles.
The median nevi count was 44 nevi, significantly more than the level seen in control subjects. Transplant recipients also had significantly more nevi in sun-exposed areas of the body, as well as on the palms and soles. Transplant recipients were more likely to have atypical nevi and to have nevi greater than 5 mm in diameter.
In addition to fair skin, factors associated with an increase in the overall nevi count included being older than age 10 at the time of the transplant and having total body irradiation, pretransplant chemotherapy, and myeloablative conditioning. Having had a sunburn since the transplant, reported by 40%, was also a risk factor.
Chronic GVHD and chronic GVHD of the skin were associated with the presence of atypical nevi; acute GVHD, the duration of immune suppression, and the use of topical steroids or calcineurin inhibitors were not associated with increased risk of atypical nevi.
She and her coinvestigators are currently analyzing the pathogenesis of these late effects in this population, and autoimmune skin conditions – vitiligo and alopecia – in 25% of the transplant recipients in the study.
In 2013, 1,100 children under aged 16 years in the United States underwent a bone marrow transplant, she noted.
Dr. Sheu had no disclosures.
AT AAD 16
Key clinical point: Children who have had a hematopoietic stem cell transplant need to have routine skin exams and be educated about sun protection needs.
Major finding: 41% of the transplant recipients had at least one actinic keratosis, a basal or squamous cell carcinoma, or a solar lentigo; 11% had at least one nevus spilus.
Data source: A single-center study of 85 posttransplant patients and 85 healthy controls who were matched by age, gender, and Fitzpatrick skin type.
Disclosures: The study was not sponsored and Dr. Sheu had no disclosures.
Ibrutinib approved as first-line therapy for all CLL patients
Ibrutinib (Imbruvica) has been approved as a first-line treatment for patients with chronic lymphocytic leukemia (CLL), irrespective of their treatment history, according to a statement issued by the manufacturer, AbbVie.
The approval is based on data from the randomized, multicenter, open-label phase III RESONATE-2 trial, which evaluated the use of ibrutinib versus chlorambucil in 269 treatment-naive patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were presented at the 2015 annual meeting of the American Society of Hematology.
“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” Dr. Jan Burger of the University of Texas MD Anderson Cancer Center, Houston, and the lead investigator of RESONATE-2, said in the AbbVie statement. “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”
The National Comprehensive Cancer Network also recently published an update to its clinical practice guidelines for non-Hodgkin’s lymphomas, granting Imbruvica a category 1 recommendation for certain CLL patients, including as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities, the AbbVie statement noted.
Imbruvica has been jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and by Janssen Biotech.
Ibrutinib (Imbruvica) has been approved as a first-line treatment for patients with chronic lymphocytic leukemia (CLL), irrespective of their treatment history, according to a statement issued by the manufacturer, AbbVie.
The approval is based on data from the randomized, multicenter, open-label phase III RESONATE-2 trial, which evaluated the use of ibrutinib versus chlorambucil in 269 treatment-naive patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were presented at the 2015 annual meeting of the American Society of Hematology.
“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” Dr. Jan Burger of the University of Texas MD Anderson Cancer Center, Houston, and the lead investigator of RESONATE-2, said in the AbbVie statement. “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”
The National Comprehensive Cancer Network also recently published an update to its clinical practice guidelines for non-Hodgkin’s lymphomas, granting Imbruvica a category 1 recommendation for certain CLL patients, including as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities, the AbbVie statement noted.
Imbruvica has been jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and by Janssen Biotech.
Ibrutinib (Imbruvica) has been approved as a first-line treatment for patients with chronic lymphocytic leukemia (CLL), irrespective of their treatment history, according to a statement issued by the manufacturer, AbbVie.
The approval is based on data from the randomized, multicenter, open-label phase III RESONATE-2 trial, which evaluated the use of ibrutinib versus chlorambucil in 269 treatment-naive patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older. The RESONATE-2 data were presented at the 2015 annual meeting of the American Society of Hematology.
“The progression-free survival data seen in these previously untreated CLL patients are strong and encouraging,” Dr. Jan Burger of the University of Texas MD Anderson Cancer Center, Houston, and the lead investigator of RESONATE-2, said in the AbbVie statement. “This is especially important for first-line CLL patients, when considering the safety profile. This treatment represents another option for these patients.”
The National Comprehensive Cancer Network also recently published an update to its clinical practice guidelines for non-Hodgkin’s lymphomas, granting Imbruvica a category 1 recommendation for certain CLL patients, including as a first-line treatment option for frail CLL patients with significant comorbidities, as well as for CLL patients with or without del 17p or the genetic mutation TP53 who are 70 years or older, or younger patients with significant comorbidities, the AbbVie statement noted.
Imbruvica has been jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and by Janssen Biotech.
Targeting a protein to prevent malignancy
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
Photo by Aaron Logan
New research suggests hematologic malignancies driven by MYC might be prevented by lowering levels of another protein, MCL-1.
“Our colleagues had previously discovered that reducing the activity of MCL-1 is a promising strategy to treat malignant MYC-driven cancers,” said Stephanie Grabow, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia.
“We have now shown that the same approach might be able to prevent those cancers from forming in the first place.”
Dr Grabow and her colleagues described this work in Cell Reports.
Previous research indicated that expression from both MCL-1 alleles is essential for the survival of hematopoietic stem and progenitor cells during stress-induced repopulation of the hematopoietic system.
So, with this study, Dr Grabow and her colleagues set out to determine whether reducing MCL-1 protein levels might hinder the development of hematologic malignancies.
In experiments with mice, the investigators found that loss of one MCL-1 allele significantly delayed the development of MYC-driven lymphoma and reduced MYC-driven accumulation of pre-leukemic cancer-initiating cells.
However, loss of one p53 allele accelerated MYC-driven lymphomagenesis even when one MCL-1 allele was deleted. Loss of PUMA accelerated lymphoma development as well, though to a much lesser extent.
Loss of BIM substantially accelerated lymphomagenesis when one MCL-1 allele was deleted, restoring lymphoma-initiating cells and the rate of tumor development.
And loss of one BIM allele overrode the survival defect observed in pre-leukemic Eμ-Myc B-cell progenitors when one MCL-1 allele was deleted.
The investigators noted that loss of one MCL-1 allele did not noticeably impair the survival of normal B lymphoid cells even though it greatly diminished the survival of MYC-overexpressing B-cell progenitors.
“No one had realized just how vulnerable cells undergoing cancerous changes are to a relatively minor reduction in the levels of MCL-1,” Dr Grabow said.
“We found that MCL-1 is critical for keeping developing cancer cells alive through the stressful events that cause the transformation of a healthy cell into a cancerous cell. This result is particularly exciting because MCL-1 inhibitors are already in development as anticancer drugs.”
Study investigator Brandon Aubrey, MBBS, also of the Walter and Eliza Hall Institute, said this research could inform future strategies to prevent cancer.
“Early treatment or even cancer prevention are likely to be a more effective way to fight cancer than treating an established cancer after it has already formed and made a person sick,” he said. ”Our research has suggested that dependency on MCL-1 could be a key vulnerability of many developing cancers.”
“In the future, MCL-1 inhibitors might have potential benefit for treating the very early stages of MYC-driven cancers, or we may even be able use these agents to prevent people from getting cancer in the first place.”
FDA approves ibrutinib as first-line CLL therapy
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Photo courtesy of Janssen
The US Food and Drug Administration (FDA) has approved the BTK inhibitor ibrutinib (Imbruvica) as a first-line treatment for patients with chronic lymphocytic leukemia (CLL).
This means ibrutinib is now FDA-approved to treat CLL patients regardless of their treatment history, including patients with 17p deletion.
Ibrutinib is also FDA-approved to treat Waldenström’s macroglobulinemia, and the drug was granted accelerated approval to treat patients with mantle cell lymphoma who have received at least 1 prior therapy.
Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc. For more details on the drug, see the full prescribing information, available at imbruvica.com.
RESONATE-2 trial
The latest FDA approval for ibrutinib is based on results from the phase 3 RESONATE-2 trial (PCYC-1115), which were presented at the 2015 ASH Annual Meeting and simultaneously published in NEJM.
RESONATE-2 enrolled 269 treatment-naïve patients with CLL or small lymphocytic lymphoma who were 65 or older.
Patients were randomized to receive ibrutinib (n=136) at 420 mg once a day until progression or unacceptable toxicity, or chlorambucil (n=133) on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in cycle 1 was 0.5 mg/kg and was increased based on tolerability in cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg.
The primary endpoint of the study was progression-free survival (PFS), as assessed by an independent review committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis.
Key secondary endpoints included overall response rate (based on the same iWCLL criteria), overall survival (OS), and safety.
Ibrutinib significantly prolonged PFS, as determined by the IRC, reducing the risk of progression or death by 84% compared to chlorambucil. The hazard ratio was 0.16 (P<0.001). The median PFS was not reached in the ibrutinib arm but was 18.9 months for the chlorambucil arm.
Ibrutinib significantly prolonged OS as well, although the median OS was not reached in either treatment arm. The OS rate at 24 months was 98% with ibrutinib and 85% with chlorambucil. The relative risk of death with ibrutinib was 84% lower than that with chlorambucil. The hazard ratio was 0.16 (P=0.001).
Ibrutinib was associated with a significantly higher IRC-assessed overall response rate compared to chlorambucil—82% and 35%, respectively (P<0.0001). Five patients (4%) in the ibrutinib arm achieved a complete response, as did 2 patients (2%) in the chlorambucil arm.
The median duration of treatment was 17.4 months in the ibrutinib arm and 7.1 months in the chlorambucil arm.
The most common adverse events of any grade—in the ibrutinib and chlorambucil arms, respectively—were diarrhea (42% and 17%), fatigue (30% and 38%), cough (22% and 15%), nausea (22% and 39%), peripheral edema (19% and 9%), dry eye (17% and 5%), arthralgia (16% and 7%), neutropenia (16% and 23%), and vomiting (13% and 20%).
Adverse events of grade 3 or higher—in the ibrutinib and chlorambucil arms, respectively—were neutropenia (10% and 18%), anemia (6% and 8%), hypertension (4% and 0%), pneumonia (4% and 2%), diarrhea (4% and 0%), maculopapular rash (3% and 2%), decreased platelet count (3% and 1%), abdominal pain (3% and 1%), hyponatremia (3% and 0%), thrombocytopenia (2% and 6%), febrile neutropenia (2% and 2%), upper respiratory tract infection (2% and 2%), pleural effusion (2% and 1%), cellulitis (2% and 0%), fatigue (1% and 5%), syncope (1% and 2%), and hemolytic anemia (0% and 2%).
Changes in chromosome structure contribute to T-ALL, other cancers
acute lymphoblastic leukemia
Image by Hind Medyouf
Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.
These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.
In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.
“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.
These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.
By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.
All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.
The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.
Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.
By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.
The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.
“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”
The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.
“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.
“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”
In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.
The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.
“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.
acute lymphoblastic leukemia
Image by Hind Medyouf
Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.
These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.
In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.
“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.
These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.
By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.
All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.
The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.
Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.
By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.
The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.
“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”
The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.
“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.
“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”
In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.
The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.
“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.
acute lymphoblastic leukemia
Image by Hind Medyouf
Breaches in looping chromosomal structures known as insulated neighborhoods can activate oncogenes capable of fueling aggressive tumor growth, according to research published in Science.
These neighborhood breaches were particularly frequent in T-cell acute lymphoblastic leukemia (T-ALL) and esophageal and liver carcinoma.
In some cases, the breaches allowed enhancer elements to activate previously silent oncogenes.
“This new understanding of the role of chromosome structure in cancer gene misregulation reveals the powerful influence of the genome’s structure in human health and disease,” said study author Richard Young, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts.
These findings build on previous work in which Dr Young and his colleagues charted human genome structure and described its influence on gene control in healthy cells.
By mapping the genome’s 3-dimensional conformation, the researchers found that key genes controlling cell identity are found in insulated neighborhoods, whose loops are maintained through anchor sites bound by the protein CTCF.
All essential gene regulation, including the control of proper activation and repression, takes place within these enclosed neighborhoods.
The researchers also found these CTCF loop anchor sites are maintained across various cell types in the human body and are highly conserved in primate genomes. Such widespread structural conservation led the team to hypothesize that disruptions in genome conformation might be associated with disease, including cancers.
Sure enough, subsequent systematic genomic analysis of more than 50 cancer cell types revealed mutations affecting CTCF anchor sites, which led to the loss of insulated neighborhood boundaries.
By mapping insulated neighborhoods in T-ALL, the researchers found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes.
The team also found the genomes of esophageal and liver carcinoma samples were enriched for boundary CTCF site mutations. The genes located in the most frequently mutated neighborhoods included known proto-oncogenes and genes not previously associated with these malignancies.
“We hadn’t known if these types of mutations contributed to cancer,” Dr Young said. “Now, we have multiple examples where these disruptions activate oncogenes that play major roles in tumorigenesis.”
The researchers noted that this oncogenic mechanism may be valuable for identifying genes that drive poorly understood cancers.
“In some cancers, such as esophageal carcinoma, the most frequent genetic mutation occurs at the CTCF sites, which is quite striking,” said Denes Hnisz, PhD, a researcher in the Young lab.
“In addition, there are still many cancers whose driver mutations and oncogenes are not known, and mapping altered structures may reveal the key oncogenes in these cancers.”
In an attempt to confirm the relationship between structural disruption and oncogenesis, the researchers used genome editing techniques to introduce CTCF anchor site deletions in non-malignant cells. They found these mutations were sufficient to activate oncogenes that are silent in normal cells.
The researchers said these findings suggest future mapping of genome structure in individual cancer patients might improve diagnosis and help guide treatment protocols.
“Now that we understand how perturbations in the genome’s structure can contribute to oncogenesis, we’re developing strategies to efficiently diagnose and potentially fix these faulty neighborhoods,” said Abe Weintraub, a graduate student in the Young lab.
Team identifies potential target for aggressive AML
Photo by Rhoda Baer
Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).
Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.
The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.
And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.
To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.
HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.
“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.
“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”
The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.
Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).
“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”
Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.
“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”
Photo by Rhoda Baer
Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).
Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.
The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.
And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.
To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.
HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.
“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.
“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”
The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.
Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).
“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”
Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.
“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”
Photo by Rhoda Baer
Research published in The Journal of Clinical Investigation has revealed a potential therapeutic target for an aggressive form of acute myeloid leukemia (AML).
Investigators studied AML characterized by overexpression of the gene meningioma-1 (MN1), which is not a druggable target.
The team found that MN1 overexpression induces aggressive AML that is dependent on a gene expression program controlled by 2 histone methyltransferases.
And 1 of these histone methyltransferases can be targeted by drugs currently in clinical development.
To make these discoveries, the investigators forced expression of MN1 in mice, which induced AML, and looked for changes in other genes. They found that MN1 overexpression prompted the activation of genes already linked to AML development—HoxA9 and Meis1.
HoxA9 and Meis1 are key targets of the histone methyltransferases Mll1 and Dot1l. It turned out that Mll1 and Dotl1 are essential for creating the environment MN1 needs to cause AML.
“In mice, we put MN1 in first, leading to AML,” explained study author Kathrin Bernt, MD, of the University of Colorado Anschutz Medical Campus.
“Then, we knocked out these chromatin-regulating molecules, Mll1 or Dot1l. When we did that, the leukemia collapsed.”
The investigators also studied samples from AML patients and found that samples with overexpression of MN1 and HOXA9 were sensitive to the DOT1L inhibitor EPZ004777. The drug induced dose-dependent decreases in cell growth and the fraction of cycling cells, as well as an increase in apoptosis.
Anticancer agents targeting DOT1L are already in clinical trials. One such inhibitor, EPZ-5676, is being tested in a phase 1 trial of pediatric patients with aggressive leukemias (NCT02141828).
“The existing trial targets patients with rearrangements in the gene MLL1,” Dr Bernt noted. “Our study shows another subset of patients that may benefit from this or other therapies aimed at DOT1L inhibition—namely, patients with MN1 overexpression.”
Dr Bernt added, however, that the investigators must still determine the cutoff of MN1 overexpression at which AML is susceptible to DOT1L inhibition.
“Overexpression exists along a spectrum,” she explained. “At what degree of MN1 overexpression does it become clinically significant?”