title: Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors.
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.
authors.affiliation: Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Tony A
authors.initials: TA
authors.lastname: Navas
authors.forename: Mani
authors.initials: M
authors.lastname: Mohindru
authors.forename: Myka
authors.initials: M
authors.lastname: Estes
authors.forename: Jing Ying
authors.initials: JY
authors.lastname: Ma
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Perry
authors.initials: P
authors.lastname: Pahanish
authors.forename: Simrit
authors.initials: S
authors.lastname: Parmar
authors.forename: Edwin
authors.initials: E
authors.lastname: Haghnazari
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Robert
authors.initials: R
authors.lastname: Collins
authors.forename: Irene
authors.initials: I
authors.lastname: Kerr
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Nguyen
authors.forename: Yin
authors.initials: Y
authors.lastname: Xu
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Alan A
authors.initials: AA
authors.lastname: List
authors.forename: Linda S
authors.initials: LS
authors.lastname: Higgins
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000201:enzymology* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000201:enzymology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D012307:Risk Factors; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D007527:Isoenzymes; D034741:RNA, Small Interfering; C499748:SCIO-469; D048051:p38 Mitogen-Activated Protein Kinases