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

The tumor suppressor 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 elici...

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Published in:Science advances 2023-12, Vol.9 (48), p.eadh1436-eadh1436
Main Authors: Nishida, Yuki, Ishizawa, Jo, Ayoub, Edward, Montoya, Rafael Heinz, Ostermann, Lauren B, Muftuoglu, Muharrem, Ruvolo, Vivian R, Patsilevas, Tallie, Scruggs, Darah A, Khazaei, Shayaun, Mak, Po Yee, Tao, Wenjing, Carter, Bing Z, Boettcher, Steffen, Ebert, Benjamin L, Daver, Naval G, Konopleva, Marina, Seki, Takahiko, Kojima, Kensuke, Andreeff, Michael
Format: Article
Language:English
Subjects:
Apoptosis - genetics
Biomedicine and Life Sciences
Cancer
Cell Line, Tumor
Humans
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - pathology
Proto-Oncogene Proteins c-mdm2 - genetics
Proto-Oncogene Proteins c-mdm2 - metabolism
SciAdv r-articles
Tumor Suppressor Protein p53 - genetics
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Summary:The tumor suppressor 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. regulates , 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.
ISSN:2375-2548
2375-2548
DOI:10.1126/SCIADV.ADH1436