Abdul-Aziz, AM;
Shafat, MS;
Sun, Y;
Marlein, CR;
Piddock, RE;
Robinson, SD;
Edwards, DR;
... Rushworth, SA; + view all
(2018)
HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia.
Oncogene
, 37
(20)
pp. 2676-2686.
10.1038/s41388-018-0151-1.
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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.
| Type: | Article |
|---|---|
| Title: | HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41388-018-0151-1 |
| Publisher version: | https://doi.org/10.1038/s41388-018-0151-1 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10062038 |
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