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

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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

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Myelodysplastic Syndromes
Hematopoiesis
p38 Mitogen-Activated Protein Kinases
Bone
Apoptosis
Refractory materials
Small Interfering RNA
Protein Isoforms
Chemical activation
Molecules
Bone Marrow
SCIO-469
Hematologic Diseases
Down-Regulation

ASJC Scopus subject areas

  • Hematology

Cite this

Navas, T. A., Mohindru, M., Estes, M., Jing, Y. M., Sokol, L., Pahanish, P., ... 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

Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. / Navas, Tony A.; Mohindru, Mani; Estes, Myka; Jing, Ying Ma; Sokol, Lubomir; Pahanish, Perry; Parmar, Simrit; Haghnazari, Edwin; Zhou, Li; Collins, Robert; Kerr, Irene; Nguyen, Aaron N.; Xu, Yin; Platanias, Leonidas C.; List, Alan A.; Higgins, Linda S.; Verma, Amit.

In: Blood, Vol. 108, No. 13, 15.12.2006, p. 4170-4177.

Research output: Contribution to journalArticle

Navas, TA, Mohindru, M, Estes, M, Jing, YM, Sokol, L, Pahanish, P, Parmar, S, Haghnazari, E, Zhou, L, Collins, R, Kerr, I, Nguyen, AN, Xu, Y, Platanias, LC, List, AA, Higgins, LS & Verma, A 2006, 'Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors', Blood, vol. 108, no. 13, pp. 4170-4177. https://doi.org/10.1182/blood-2006-05-023093
Navas TA, Mohindru M, Estes M, Jing YM, Sokol L, Pahanish P et al. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood. 2006 Dec 15;108(13):4170-4177. https://doi.org/10.1182/blood-2006-05-023093
Navas, Tony A. ; Mohindru, Mani ; Estes, Myka ; Jing, Ying Ma ; Sokol, Lubomir ; Pahanish, Perry ; Parmar, Simrit ; Haghnazari, Edwin ; Zhou, Li ; Collins, Robert ; Kerr, Irene ; Nguyen, Aaron N. ; Xu, Yin ; Platanias, Leonidas C. ; List, Alan A. ; Higgins, Linda S. ; Verma, Amit. / Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. In: Blood. 2006 ; Vol. 108, No. 13. pp. 4170-4177.
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