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Dryad

RNA sequencing of AML cells treated with milademetan, selinexor and the combination of milademetan and selinexor

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Nov 08, 2023 version files 224.16 GB

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Abstract

The tumor suppressor TP53 is frequently inactivated in cancers in a mutation-independent manner and is reactivated by inhibiting its negative regulators. We here co-target MDM2 with the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in synergistic induction of apoptosis in acute myeloid leukemia (AML). Surprisingly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome non-genetic, stress-adapted venetoclax resistance.