Background: MDM2 is elevated in multiple myeloma (MM). Although traditionally, MDM2 negatively regulates p53, a growing body of research suggests that MDM2 plays several p53-independent roles in cancer pathogenesis as a regulator of oncogene mRNA stability and translation. Yet, the molecular mechanisms underlying MDM2 overexpression and its role in drug resistance in MM remain undefined. Methods: Both myeloma cell lines and primary MM samples were employed. Cell viability, cell cycle and apoptosis assays, siRNA transfection, quantitative real-time PCR, immunoblotting, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), soft agar colony formation and migration assay, pulse-chase assay, UV cross-linking, gel-shift assay, RNA-protein binding assays, MEME-analysis for discovering c-Myc DNA binding motifs studies, reporter gene constructs procedure, gene transfection and reporter assay, MM xenograft mouse model studies, and statistical analysis were applied in this study. Results: We show that MDM2 is associated with poor prognosis. Importantly, its upregulation in primary MM samples and human myeloma cell lines (HMCLs) drives drug resistance. Inhibition of MDM2 by RNAi, or by the MDM2/XIAP dual inhibitor MX69, significantly enhanced the sensitivity of resistant HMCLs and primary MM samples to bortezomib and other anti-myeloma drugs, demonstrating that MDM2 can modulate drug response. MDM2 inhibition resulted in a remarkable suppression of relapsed MM cell growth, colony formation, migration and induction of apoptosis through p53-dependent and -independent pathways. Mechanistically, MDM2 was found to reciprocally regulate c-Myc in MM; MDM2 binds to AREs on c-Myc 3′UTR to increase c-Myc mRNA stability and translation, while MDM2 is a direct transcriptional target of c-Myc. MDM2 inhibition rendered c-Myc mRNA unstable, and reduced c-Myc protein expression in MM cells. Importantly, in vivo delivery of MX69 in combination with bortezomib led to significant regression of tumors and prolonged survival in an MM xenograft model. Conclusion: Our findings provide a rationale for the therapeutic targeting of MDM2/c-Myc axis to improve clinical outcome of patients with refractory/relapsed MM.

TP53 mutations are associated with extremely poor outcomes in acute myeloid leukemia (AML). The outcomes of patients with TP53-mutated (TP53MUT) AML after different frontline treatment modalities are not well established. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative procedure for AML; however, long-term outcomes among patients with TP53MUT AML after allo-HCT are dismal, and the benefit of allo-HCT remains controversial. We sought to evaluate the outcomes of patients with TP53MUT AML after treatment with different frontline induction therapies and allo-HCT. A total of 113 patients with TP53MUT AML were retrospectively evaluated. Patients with TP53MUT AML who received intensive or azacitidine-venetoclax induction had higher complete remission rates compared to patients treated with other hypomethylating-agent-based induction regimens. However, OS and EFS were not significantly different among the induction regimen groups. Allo-HCT was associated with improved OS and EFS among patients with TP53MUT AML; however, allo-HCT was not significantly associated with improved OS or EFS in time-dependent or landmark analysis. While the outcomes of all patients were generally poor irrespective of therapeutic strategy, transplanted patients with lower TP53MUT variant allele frequency (VAF) at the time of diagnosis had superior outcomes compared to transplanted patients with higher TP53 VAF. Our study provides further evidence that the current standards of care for AML confer limited therapeutic benefit to patients with TP53 mutations.

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Background Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) generally confers poor prognosis, however, patient outcomes are heterogeneous. The impact of TP53 allelic state and variant allele frequency (VAF) in AML‐MRC remains poorly defined. Methods We retrospectively evaluated 266 AML‐MRC patients who had NGS testing at our institution from 2014 to 2020 and analyzed their clinical outcomes based on clinicopathological features. Results TP53 mutations were associated with cytogenetic abnormalities in 5q, 7q, 17p, and complex karyotype. Prognostic evaluation of TP53 MUT AML‐MRC revealed no difference in outcome between TP53 double/multi‐hit state and single‐hit state. Patients with high TP53 MUT variant allele frequency (VAF) had inferior outcomes compared to patients with low TP53 MUT VAF. When compared to TP53 WT patients, TP53 MUT patients had inferior outcomes regardless of MRC‐defining criteria, TP53 allelic state, or VAF. TP53 mutations and elevated serum LDH were independent predictors for inferior OS and EFS, while PHF6 mutations and transplantation were independent predictors for favorable OS and EFS. NRAS mutation was an independent predictor for favorable EFS. Conclusions Our study suggests that TP53 MUT AML‐MRC defines a very‐high‐risk subentity of AML in which novel therapies should be explored.