Insights into KMT2A rearrangements in acute myeloid leukemia: from molecular characteristics to targeted therapies.

Acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2A-r) represents a highly aggressive and prognostically unfavorable subtype of leukemia, often resistant to standard treatments and associated with high relapse rates. KMT2A-r, found in 3-10% of adult AML cases, disrupt epigenetic regulation by forming chimeric proteins that activate oncogenic pathways like HOXA and MEIS1. These fusion proteins recruit cofactors such as Menin and DOT1L, driving leukemogenesis through abnormal histone methylation. Diagnosing KMT2A-r AML requires precision, with traditional methods like FISH and RT-PCR being complemented by advanced technologies such as next-generation sequencing (NGS) and machine learning (ML). ML models, leveraging transcriptomic data, can predict KMT2A-r and identify biomarkers like LAMP5 and SKIDA1, improving risk stratification. Therapeutically, there is a shift from chemotherapy to targeted therapies. Menin inhibitors (e.g., Revumenib, Ziftomenib) disrupt the Menin-KMT2A interaction, suppressing HOXA/MEIS1 and promoting differentiation. DOT1L inhibitors (e.g., Pinometostat) show promise in combination therapies, while novel approaches like WDR5 inhibitors and PROTAC-mediated degradation are expanding treatment options. Despite progress, challenges remain, including optimizing minimal residual disease monitoring, overcoming resistance, and validating biomarkers. This review emphasizes the imperative to translate molecular insights into personalized therapeutic regimens, offering renewed hope for patients afflicted by this historically refractory malignancy.