Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors

Tony A. Navas, Mani Mohindru, Myka Estes, Ying Ma Jing, 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, Amit Verma

Research output: Contribution to journalArticle

99 Scopus citations

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 p38α 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 p38α 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.

Original languageEnglish (US)
Pages (from-to)4170-4177
Number of pages8
JournalBlood
Volume108
Issue number13
DOIs
StatePublished - Dec 15 2006

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Navas, T. A., Mohindru, M., Estes, M., Jing, Y. M., Sokol, L., Pahanish, P., Parmar, S., Haghnazari, E., Zhou, L., Collins, R., Kerr, I., Nguyen, A. N., Xu, Y., Platanias, L. C., List, A. A., Higgins, L. S., & Verma, A. (2006). Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood, 108(13), 4170-4177. https://doi.org/10.1182/blood-2006-05-023093