Distinct Responses to Menin Inhibition and Synergy with DOT1L Inhibition in KMT2A -Rearranged Acute Lymphoblastic and Myeloid Leukemia.
Fabienne R S AdriaansePauline SchneiderSusan T C J M Arentsen-PetersAna M Neves da FonsecaJanine StutterheimRob PietersC Michel ZwaanRonald W StamPublished in: International journal of molecular sciences (2024)
Pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) exhibit favorable survival rates. However, for AML and ALL patients carrying KMT2A gene translocations clinical outcome remains unsatisfactory. Key players in KMT2A-fusion-driven leukemogenesis include menin and DOT1L. Recently, menin inhibitors like revumenib have garnered attention for their potential therapeutic efficacy in treating KMT2A -rearranged acute leukemias. However, resistance to menin inhibition poses challenges, and identifying which patients would benefit from revumenib treatment is crucial. Here, we investigated the in vitro response to revumenib in KMT2A -rearranged ALL and AML. While ALL samples show rapid, dose-dependent induction of leukemic cell death, AML responses are much slower and promote myeloid differentiation. Furthermore, we reveal that acquired resistance to revumenib in KMT2A -rearranged ALL cells can occur either through the acquisition of MEN1 mutations or independently of mutations in MEN1 . Finally, we demonstrate significant synergy between revumenib and the DOT1L inhibitor pinometostat in KMT2A -rearranged ALL, suggesting that such drug combinations represent a potent therapeutic strategy for these patients. Collectively, our findings underscore the complexity of resistance mechanisms and advocate for precise patient stratification to optimize the use of menin inhibitors in KMT2A -rearranged acute leukemia.
Keyphrases
- acute myeloid leukemia
- end stage renal disease
- acute lymphoblastic leukemia
- allogeneic hematopoietic stem cell transplantation
- newly diagnosed
- cell death
- ejection fraction
- chronic kidney disease
- peritoneal dialysis
- prognostic factors
- liver failure
- hepatitis b virus
- immune response
- risk assessment
- dna methylation
- respiratory failure
- oxidative stress
- quantum dots
- human health
- anti inflammatory
- pi k akt
- acute respiratory distress syndrome