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Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia
Jolieke G. van Oosterwijk, … , Navjotsingh Pabla, Sharyn D. Baker
Jolieke G. van Oosterwijk, … , Navjotsingh Pabla, Sharyn D. Baker
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):369-380. https://doi.org/10.1172/JCI91893.
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Research Article Hematology Oncology Article has an altmetric score of 4

Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia

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Abstract

Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3–internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq–based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD–positive (FLT3-ITD+) model of sorafenib resistance. Mechanistically, the antiangiogenic effects of sorafenib led to increased bone marrow hypoxia, which contributed to HIF-dependent BMX upregulation. In in vitro experiments, hypoxia-dependent BMX upregulation was observed in both AML and non-AML cell lines. Functional studies in human FLT3-ITD+ cell lines showed that BMX is part of a compensatory signaling mechanism that promotes AML cell survival during FLT3 inhibition. Taken together, our results demonstrate that hypoxia-dependent upregulation of BMX contributes to therapeutic resistance through a compensatory prosurvival signaling mechanism. These results also reveal the role of off-target drug effects on tumor microenvironment and development of acquired drug resistance. We propose that the bone marrow niche can be altered by anticancer therapeutics, resulting in drug resistance through cell-nonautonomous microenvironment-dependent effects.

Authors

Jolieke G. van Oosterwijk, Daelynn R. Buelow, Christina D. Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A. Shurtleff, Laura J. Janke, Stanley Pounds, Jeffrey E. Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D. Baker

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Figure 4

VEGF inhibition is sufficient to induce BMX expression in a MOLM13 FLT3-ITD+ xenograft model.

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VEGF inhibition is sufficient to induce BMX expression in a MOLM13 FLT3-...
Mice engrafted with MOLM13 cells were treated with vehicle or sorafenib for 5 days, after which the hind limbs were embedded in paraffin for assessment of percentage vessel area over total bone marrow area using CD31 staining. (A) Representative images of bone marrow histology and CD31 staining (original magnification, ×40) from mice treated with vehicle (n = 12) or sorafenib (n = 12). More than 3 fields were analyzed for each sample per mouse. Scale bar: 50 µM. (B) The decrease in vessel area in mice treated with sorafenib indicates an increase in hypoxia (*P = 0.002, Welch’s t test). (C) Starting on day 5 after injection of MOLM13 FLT3-ITD+ cells, NSG mice were treated with vehicle, sorafenib, bevacizumab, or B20. On day 10 of sorafenib treatment and day 13 of bevacizumab or B20 treatment, Western blot analysis of bone marrow showed that B20-mediated VEGF inhibition was sufficient to induce BMX upregulation in MOLM13 cells. Western blots are from 1 experiment.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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