Abstract
The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low-risk MDS and correlates with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacologic inhibition of p38alpha by a novel small molecule inhibitor, SCIO-469, decreases apoptosis in MDS CD34+ progenitors and leads to dose-dependant increases in erythroid and myeloid colony formation. Down-regulation of the dominant p38alpha isoform by siRNA also leads to enhancement of hematopoiesis in MDS bone marrow progenitors in vitro. These data implicate p38 MAPK in the pathobiology of ineffective hematopoiesis in lowrisk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS.
Publication types
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Clinical Trial
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Multicenter Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Aged, 80 and over
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Apoptosis / drug effects
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Bone Marrow / enzymology*
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Bone Marrow / pathology
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Down-Regulation / drug effects
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Female
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Hematopoiesis* / drug effects
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Humans
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Indoles / pharmacology*
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Indoles / therapeutic use
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Male
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Middle Aged
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Myelodysplastic Syndromes / drug therapy
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Myelodysplastic Syndromes / enzymology*
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Myelodysplastic Syndromes / pathology
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Myeloid Progenitor Cells / enzymology*
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Myeloid Progenitor Cells / pathology
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / pathology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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Risk Factors
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Tumor Cells, Cultured
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Indoles
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Isoenzymes
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RNA, Small Interfering
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SCIO-469
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p38 Mitogen-Activated Protein Kinases