Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors.
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.
Navas
Tony A
TA
Albert Einstein College of Medicine, Bronx, NY, USA.
Mohindru
Mani
M
Estes
Myka
M
Ma
Jing Ying
JY
Sokol
Lubomir
L
Pahanish
Perry
P
Parmar
Simrit
S
Haghnazari
Edwin
E
Zhou
Li
L
Collins
Robert
R
Kerr
Irene
I
Nguyen
Aaron N
AN
Xu
Yin
Y
Platanias
Leonidas C
LC
List
Alan A
AA
Higgins
Linda S
LS
Verma
Amit
A
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
D007211:Indoles; D007527:Isoenzymes; D034741:RNA, Small Interfering; C499748:SCIO-469; D048051:p38 Mitogen-Activated Protein Kinases