Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias

• DOI: 10.1126/sciadv.adh1436
• Publication Date: 2023-11-29T19:00:24Z
• Authors: Yuki Nishida; Jo Ishizawa; Edward Ayoub; Rafael Heinz Montoya; Lauren B. Ostermann; Muharrem Muftuoglu; Vivian R Ruvolo; Tallie Patsilevas; Darah A. Scruggs; Shayaun Khazaei; Po Yee Mak; Wenjing Tao; Bing Z. Carter; Steffen Boettcher; Benjamin L. Ebert; Naval G. Daver; Marina Konopleva; Takahiko Seki; Kensuke Kojima; Michael Andreeff
• Keywords: Venetoclax

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