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Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.” 
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”
Inflammatory signaling in mesenchymal niche cells can be used to predict the transformation from pre-leukemic syndrome to acute myeloid leukemia (AML), according to preclinical research published in Cell Stem Cell.
“This discovery sheds new light on the long-standing association between inflammation and cancer,” said study author Marc Raaijmakers, MD, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands.
“The elucidation of the molecular mechanism underlying this concept opens the prospect of improved diagnosis of patients at increased risk for the development of leukemia and the potential of future, niche-targeted therapy to delay or prevent the development of leukemia.”
In a previous study, Dr Raaijmakers and his colleagues discovered that mutations in mesenchymal progenitor cells can induce myelodysplasia in mice and promote the development of AML.
With the current study, the researchers wanted to build upon those findings by identifying the underlying mechanisms and determining their relevance to human disease.
So the team performed massive parallel RNA sequencing of mesenchymal cells in mice with Shwachman-Diamond syndrome and bone marrow samples from patients with Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and myelodysplastic syndromes (MDS).
The researchers found that mesenchymal cells in these pre-leukemic disorders are under stress. The stress leads to the release of inflammatory molecules called S100A8 and S100A9, which cause mitochondrial and DNA damage in hematopoietic stem and progenitor cells.
The team also found that activation of this inflammatory pathway in mesenchymal cells predicted the development of AML and clinical outcomes in patients with MDS.
Leukemic evolution occurred in 29.4% (5/17) of MDS patients whose mesenchymal cells overexpressed S100A8/9 and 14.2% (4/28) of MDS patients without S100A8/9 overexpression.
The time to leukemic evolution and the length of progression-free survival were both significantly shorter in niche S100A8/9+ patients than niche S100A8/9- patients.
The average time to leukemic evolution was 3.4 months and 18.5 months, respectively (P=0.03). And the median progression-free survival was 11.5 months and 53 months, respectively (P=0.03)
The researchers believe these findings, if confirmed in subsequent studies, could lead to the development of tests to identify patients with pre-leukemic syndromes who have a high risk of developing AML.
“These high-risk patients could be treated more aggressively at an earlier stage, thereby preventing or slowing down disease progression,” Dr Raaijmakers said. “Moreover, the findings suggest that new drugs targeting the inflammatory pathway should be tested in future preclinical studies.”