Inhibition of CRM1 reverses hypoxia-driven chemoresistance in acute myeloid leukemia via overcoming HIF-1α-mediated lysosomal sequestration.

ABSTRACT:

Introduction

In relapsed/refractory acute myeloid leukemia (R/R-AML), hypoxia-driven chemoresistance is orchestrated by HIF-1α-induced P-glycoprotein (P-gp) overexpression and subsequent lysosomal sequestration of anthracyclines. Nuclear-cytoplasmic shuttling of the HIF-1α prolyl-hydroxylase PHD2 is controlled by chromosome region maintenance 1 (CRM1), which is frequently up-regulated in AML; however, whether pharmacologic CRM1 inhibition restores PHD2 nuclear availability to accelerate HIF-1α degradation and reverse chemoresistance remains undefined.

Methods

AML cell lines (MV4-11 and MOLM13) were cultured under normoxic or hypoxic conditions. The effects of hypoxia on drug sensitivity, intracellular drug distribution, and protein expression were assessed using CCK-8 assays

SUBMITTER: Feng X 

PROVIDER: S-EPMC12696167 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature