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

Oncogene
Amina Abdul-AzizStuart A Rushworth

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.

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Citations

Mar 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eugenio CavalliMaria Sofia Basile
Jun 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Adam J LambleEvan F Lind
Jul 3, 2021·International Journal of Molecular Sciences·Samantha BrunoSimona Soverini
Jul 12, 2021·Experimental Hematology & Oncology·Yiyi YaoHuafeng Wang
Sep 9, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hsin-Yu ChungChin-Hwa Hu

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Datasets Mentioned

BETA
GSE49642

Methods Mentioned

BETA
xenograft
ELISA
Assay
PCR
electrophoresis

Software Mentioned

Graphpad Prism5
Image J

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