HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia

Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1 alpha and HIF2 alpha, establish that hypoxia supports AML tumor proliferation through HIF1 alpha signaling. In vivo targeting of leukemic cell HIF1 alpha inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2 alpha had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1 alpha to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML.