p38MAPK inhibitors attenuate cytokine production by bone marrow stromal cells and reduce stroma-mediated proliferation of acute lymphoblastic leukemia cells

OBJECTIVE: The bone marrow microenvironment provides critical support for the growth and survival of acute lymphoblastic leukemia cells and protection against the effects of chemotherapeutic agents. Although the mechanisms are not fully understood, it is likely that they are mediated at least in part by stromal derived cytokines and chemokines. RESULTS: We have demonstrated that inhibition of p38(MAPK) in bone marrow stromal cells reduced the production of IL-6, VEGF, PDGF and CXCL12. In addition to the known role of CXCL12 in ALL cell stromal-dependent proliferation, we have shown that VEGF and PDGF also provide important proliferative cues for ALL cells, both as exogenous single agents and as bone marrow stromal culture-derived factors. In contrast we could not detect a significant role for IL-6 in ALL stromal-dependent proliferation. Consistent with these findings inhibition of p38(MAPK) significantly reduced stromal-dependent proliferation of ALL cells. METHODS: Cell proliferation was measured by (3)H-thymidine assays, survival by Annexin V/PI staining, gene expression by microarray, cytokine protein levels by antibody microarrays and/or ELISA and cellular signaling by western blotting. CONCLUSION: These findings suggest that inhibition of p38(MAPK) may provide a useful adjunct to current treatment strategies by retarding ALL cell growth.