Abstract A008: Epigenetic dynamics in KMT2A-amplified leukemia

Abstract The lysine methyltransferase KMT2A/MLL1 plays a crucial role in normal development and hematopoiesis. Rearrangement of KMT2A results in the formation of a KMT2A fusion protein with aberrant activity, which is a well-characterized driver of leukemogenesis and is therapeutically targetable. In contrast to the widely studied KMT2A translocation, the molecular consequences of other KMT2A alterations, including KMT2A amplification, remain unknown. KMT2A amplification is detected in highly aggressive and treatment-resistant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). It strongly associates with TP53 mutations and complex karyotypes. Unlike KMT2A rearrangement, KMT2A amplification is reported mostly in patients older than 65 and treated with alkylating agents. Here, we conducted a comprehensive molecular analysis of KMT2A-amplified MDS/AML by long-read nanopore sequencing. We have revealed the unique epigenetic landscape, including DNA methylation, histone modification, and chromatin accessibility, associated with KMT2A amplification. We also explored the potential of targeting KMT2A or KMT2A-medicated pathways to block leukemogenesis. These results provide a foundation for targeting the KMT2A complex in KMT2A-amplified disease, representing a promising first step toward treating MDS/AML associated with KMT2A amplification. Citation Format: Jayme Ogino, Yang Liu, Wentao Yang, Madina Sukhanova, Sheng Li, Yali Dou. Epigenetic dynamics in KMT2A-amplified leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A008.