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

Abstract

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, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling. In vivo targeting of leukemic cell HIF1α inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2α 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 HIF1α to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML.

Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia

“…Further studies are needed to better understand the functional differences in these pathways between subjects with highly proliferative vs. nonproliferative T cells. For example, hypoxia signaling promotes a protumorigenic microenvironment for many cancers, including AML, and leads to therapeutic resistance (54,55). Changes in the expression of genes involved in this pathway suggest that patients with AML may have dysregulation in the tumor immune environment in addition to variation in T cell proliferation and function.…”

Hematopoietic niche drives FLT3-ITD acute myeloid leukemia resistance to quizartinib via STAT5-and hypoxia-dependent upregulation of AXL

“…37 Hypoxia, a key factor of the microenvironment, was also reported to drive pro-tumoral signaling in AML via a HIF1α/MIF/IL8 pathway that is also thought to play a role in chronic lymphocytic leukemia survival. 38 Stroma has also been shown to sustain AML cell resistance to cytarabine via activation of the AXL receptor upon AML cell-dependent education of stroma to secrete GAS6 in vitro . 21 We now provide evidence that several microenvironment messages converge to enhance AXL expression and activation, which sustain pro-survival signals to selectively protect FLT3-ITD AML cells from quizartinib treatment in situ .…”

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

“…Additionally, it has been demonstrated that HIF-1α induces the expression of macrophage migration factor (MIF) [97], with drives interleukin-8 (IL-8) production by the BM mesenchymal stromal cells (BM-MSC), thereby supporting AML cell survival and proliferation [98]. Recently, HIF-1α has been shown to directly induce the expression of IL-8 in AML cell lines and in primary AML blasts, which in turn supports survival and proliferation of AML cells [99].…”