Transcriptomics

Dataset Information

0

Therapy-induced hypoxia contributes to AML drug-resistance through BMX Kinase upregulation


ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104594 | GEO | 2018/02/16

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2017-05-02 | PXD004442 | Pride
2022-12-07 | MSV000090855 | MassIVE
2012-02-18 | E-GEOD-35907 | biostudies-arrayexpress
2018-02-01 | E-MTAB-4487 | biostudies-arrayexpress
2022-07-07 | GSE199333 | GEO
2012-02-18 | GSE35907 | GEO
2017-12-19 | GSE95770 | GEO
2020-02-13 | GSE138057 | GEO
2020-09-02 | PXD009423 | Pride
2019-10-03 | GSE138340 | GEO