GSE104594
Therapy-induced hypoxia contributes to AML drug-resistance through BMX Kinase upregulation
Oncogenic addiction to FLT3 kinase signaling is a hallmark of FLT3-ITD+ acute myeloid leukemia (AML). While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, utilizing RNA-Seq based analysis of patient leukemic cells, we found significant up-regulation of the Tec-family kinase BMX during sorafenib resistance. BMX upregulation was recapitulated in an in vivo FLT3-ITD+ model of sorafenib resistance. Mechanistically, we found that the anti-angiogenic effects of sorafenib led to increased bone-marrow hypoxia, which contributed to HIF-dependent BMX upregulation. In in vitro experiments, hypoxia-dependent BMX up-regulation was observed in both AML and non-AML cell lines. Functional studies in FLT3-ITD+ cell lines showed that BMX is part of a compensatory signaling mechanism that promotes AML cell survival during FLT3 inhibition. Our results demonstrate that hypoxia-dependent up-regulation of BMX contributes to therapeutic resistance through a compensatory pro-survival 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 anti-cancer therapeutics, resulting in drug resistance through cell non-autonomous microenvironment-dependent effects. Overall design: eight AML samples from 4 patients, 7 are relapses and 1 is a diagnosis sample