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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4170-4177.
Prepublished online as a Blood First Edition Paper on August 29, 2006; DOI 10.1182/blood-2006-05-023093.
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Submitted May 22, 2006
Accepted July 25, 2006
Inhibition of overactivated p38 MAPK can restore
hematopoiesis in myelodysplastic syndrome progenitors
Tony A Navas, Mani Mohindru, Myka Estes, Jing Ying Ma, Lubomir Sokol, Perry Pahanish, Simrit Parmar, Edwin Haghnazari, Li Zhou, Robert Collins, Irene Kerr, Aaron N Nguyen, Yin Xu, Leonidas C Platanias, Alan A List, Linda S Higgins, and Amit Verma*
Scios Inc, Freemont, CA
Albert Einstein College of Medicine, Bronx, NY & UT SMS & DVAMC, Dallas, TX
Moffit Cancer Center, Tampa, FL
University of Texas Southwestern Medical School and Dallas Veterans Affairs Medical Ctr, Dallas, TX
Albert Einstein College of Medicine, Bronx, NY
Northwestern University Robert H Lurie Cancer Center, Chicago, IL
* Corresponding author; email: averma{at}aecom.yu.edu.
The myelodysplastic syndromes (MDS) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias due to 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 / 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, pharmacological inhibition of p38 ; 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. Downregulation of the dominant p38 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 low risk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS.
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