NPM1 (Nucleophosmin 1)

Among the older cohort, FLT3 and NPM1 mutation status, favorable karyotype, and CCI were not identified as prognostic factors. In the full cohort, using Cox proportional hazard regression and LASSO analyses for age, FLT3 and NPM1 mutation status, cytogenetic risk group, treatment site, race, primary payor, and Charleston Comorbidity Index (CCI), age (HR 65y vs 35y/=2.44, 95% CI 1.61-3.68, p<0.001) was the strongest risk factor in AML.

Additionally, CRISPR-Cas9-mediated knockdown of EPO resulted in the abrogation of cell proliferation, whereas EPOR knockdown showed no effect, suggesting that Epo promotes N2A cell proliferation through an EpoR-independent mechanism. Collectively, these findings highlight the potential of the N2A+Epo cell line as a model for identifying alternative tissue-protective Epo receptors.

Among them, revumenib and ziftomenib have advanced furthest in clinical testing. Ongoing trials are now evaluating menin inhibitors in rational combinations, frontline regimens, and maintenance therapy. Collectively, these advances highlight menin inhibition as a transformative strategy in acute leukemia, reshaping therapy through precision-targeted epigenetic intervention.

NPM1class II is instead associated with resistance to allogeneic T cells in an ex vivo co-culture assay, and importantly, dismal survival following hematopoietic stem cell transplantation. These findings provide insights into the cellular state space of AML, define diagnostic entities, and highlight potential therapeutic intervention points.

This study confirmed well-known gene-disease associations in myeloid malignancies but found no significant link between parvovirus B19 infection and specific somatic mutations or disease subtypes. These findings suggest that B19 infection may be incidental, underscoring the need for larger-scale studies to clarify its clinical relevance in patients with myeloid malignancies.

Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.

Surprisingly, we find that this combination is effective in selected AML models without mutations in MLL or NPM1, thus nominating dual inhibition of LSD1 and Menin as an attractive therapeutic approach for a mutationally diverse set of non-APL AMLs. Inhibition of LSD1 and Menin synergizes to induce differentiation of MLL-r and MLL-WT AMLs.Inhibition of Menin downregulates drivers of proliferation and stemness.Inhibition of LSD1 induces differentiation-associated inflammatory and interferon responses.LSD1 and Menin occupy different areas of the genome.

This approach predicted OS better than age, FLT3-ITD status, or morphological remission status. We propose that in the peri-transplant setting, NPM1-MRD thresholds are superior to conventional MRD analysis based on binary or log-step change data.

After stratification of patients by age, there was not a significant difference between MDSm+ and MDSm-in either younger patients (HR 0.99, p=0.98) or older patients (HR 1.42, p =0.33). These findings indicate that MDSm+ in NPM1 + AML is not independently associated with adverse risk after adjusting for age and highlight the need for age-adjusted AML risk models.

By leveraging genomic profiling and personalized engineering approaches, CAR therapies can be refined to overcome resistance and enhance precision in AML treatment. Future research should focus on integrating multiomic data to develop mutation-adapted CAR strategies, ensuring that patients receive the most effective and personalized immunotherapy.

Although the European LeukemiaNet (ELN) classifications (2017, 2022) for AML have been used to stratify outcomes for patients receiving intensive chemotherapy, application to patients receiving less intensive therapy, like azacitidine plus venetoclax, has been less satisfactory. Overall, these data support the importance of molecular sub-classification in defining treatment outcomes to venetoclax-based therapies. NCT02287233; NCT03069352.