TY - JOUR
T1 - Inhibition of p38α MAPK disrupts the pathological loop of proinflammatory factor production in the myelodysplastic syndrome bone marrow microenvironment
AU - Navas, Tony
AU - Zhou, Li
AU - Estes, Myka
AU - Haghnazari, Edwin
AU - Nguyen, Aaron
AU - Mo, Yongkai
AU - Pahanish, Perry
AU - Mohindru, Mani
AU - Cao, Tim
AU - Higgins, Linda
AU - Platanias, Leonidas C.
AU - List, Alan
AU - Verma, Amit
N1 - Funding Information:
SCIOS: We would like to thank Bruce Koppelmann, Jing Ying Ma, Heather Maecker, Gilbert O’Young, Yu-Wang Liu, and Ann M. Kapoun for their contributions to this project. This project was supported by NIH 1R01HL082946-01 and Community Foundation of Southeastern Michigan JP Mccarthy fund award to AV, NIH RO1 AG029138 to LCP and Immunology and Immunooncology Training Program T32 CA009173 to LZ.
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Cytokine production and paraneoplastic conditions neoplasia
KW - Myeloid leukemias and dysplasias neoplasia
KW - Signal transduction neoplasia
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U2 - 10.1080/10428190802322919
DO - 10.1080/10428190802322919
M3 - Article
C2 - 18949619
AN - SCOPUS:55049116044
SN - 1042-8194
VL - 49
SP - 1963
EP - 1975
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 10
ER -