Fig. 2

Regulation of gene expression by KMT2A and its rearrangements on HOXA9 and MEIS1 expression. (A) Normal KMT2A function. In a healthy cell, the KMT2A protein is split into two parts which regulate gene expression. The Menin-LEDGF complex recruits KMT2A to chromatin while the SET domain at the KMT2A-C end catalyzes H3K4 methylation, promoting gene transcription. This process turn on important genes like HOXA9 and MEIS1, which are crucial for hematopoietic differentiation and self-renewal. Other proteins, such as WDR5, ASH2L, RbBP5, DPY30, and Mof, also assist in modifying histones (as H3K36 methylation and H4K16 acetylation) to further enhance gene activity. In wild-type KMT2A, the SET domain normally regulates H3K4 methylation, which activates gene expression in a controlled manner. (B) Leukemogenic KMT2A rearrangements. In certain leukemias, KMT2A fuses with other genes. These fusion proteins retain the N-terminal but lose the SET domain, so they no longer add the H3K4 methylation mark. Instead, the fusion partners bring their own molecular properties, altering transcriptional regulation in leukemia. However, they still bind to chromatin via the Menin-LEDGF complex. Fusion partners recruitent of DOT1L complex leading to persistent and uncontrolled transcription of leukemogenic genes by H3K79 methylation. This causes continuous activation of HOXA9 and MEIS1, contributing to the development of leukemia. (C) Therapeutic approaches. New treatments are targeting these fusion proteins. Menin inhibitors disrupt its interaction with KMT2A, while DOT1L inhibitors block the aberrant H3K79 methylation. Together, they help reduce the abnormal gene expression seen in KMT2A-rearranged AML, offering a promising avenue for therapy