KMT2A-Mediated transcriptional regulation in stemness and cancer: molecular mechanisms and therapeutic opportunities

KMT2A (MLL1) is an epigenetic enzyme that activates genes via the addition of histone H3 at lysine 4 (H3K4). As a principal component of the COMPASS (complex of proteins associated with Set1), KMT2A coordinates the transcription of key developmental and lineage-specific genes, thereby shaping cellular plasticity, differentiation, and self-renewal. It is critical for regulating the balance between stem cell renewal and differentiation in both physiological and pathological aspects. Abnormal regulation or chromosomal translocations involving KMT2A are frequently implicated in hematologic malignancies and developmental disorders. In leukemias and other cancers, KMT2A fusion proteins disrupt regular transcriptional programs, creating a tumor-permissive epigenetic environment that supports stem-like properties, therapy resistance, and relapse. In addition to its canonical catalytic role, KMT2A influences chromatin remodeling, enhancer-promoter communication, and transcriptional memory, all of which are crucial for maintaining stemness and enabling cancer cell reprogramming. Given its multifaceted role in cancer and stem cell biology, KMT2A is a promising therapeutic target, and inhibitors that disrupt its interactions, enzymatic activity, or fusion pathways are showing encouraging results. Moreover, current clinical trials investigating venetoclax and menin inhibitors offer renewed hope for curative therapies. This review summarizes the current understanding of the transcriptional mechanisms and noncatalytic roles of KMT2A and the translational implications of targeting KMT2A-driven pathways in stemness and cancer, paving the way for advanced therapeutic intervention.