Inhibition of p38α MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment

Tony Navas, Li Zhou, Myka Estes, Edwin Haghnazari, Aaron Nguyen, Yongkai Mo, Perry Pahanish, Mani Mohindru, Tim Cao, Linda Higgins, Leonidas C. Platanias, Alan List, Amit Verma*

*Corresponding author for this work

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38α inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFα and IL-1β are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFα or IL-1β-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38α as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.

Original languageEnglish (US)
Pages (from-to)1963-1975
Number of pages13
JournalLeukemia and Lymphoma
Volume49
Issue number10
DOIs
StatePublished - Nov 5 2008

Keywords

  • Cytokine production and paraneoplastic conditions neoplasia
  • Myeloid leukemias and dysplasias neoplasia
  • Signal transduction neoplasia

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Navas, T., Zhou, L., Estes, M., Haghnazari, E., Nguyen, A., Mo, Y., Pahanish, P., Mohindru, M., Cao, T., Higgins, L., Platanias, L. C., List, A., & Verma, A. (2008). Inhibition of p38α MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment. Leukemia and Lymphoma, 49(10), 1963-1975. https://doi.org/10.1080/10428190802322919