Enhanced <i>TP53</i> reactivation disrupts <i>MYC</i> transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias
Yuki Nishida, Jo Ishizawa, Edward Ayoub, Rafael Heinz Montoya, Lauren B. Ostermann, Muharrem Müftüoğlu, Vivian Ruvolo, Tallie Patsilevas, Darah A. Scruggs, Shayaun Khazaei, Po Yee Mak, Wenjing Tao, Bing Z. Carter, Steffen Boettcher, Benjamin L. Ebert, Naval Daver, Marina Konopleva, Takahiko Seki, Kensuke Kojima, Michael Andreeff
Abstract
The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and 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 the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, 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 nongenetic, stress-adapted venetoclax resistance.