ISSN 2997-1036
International Journal of Hematology | Vol. 15, No. 7, July 2024 | pp. 49–56
DOI: 10.46882/2024/IJH/000173
Review Article
Title: Structural mechanics and targeted biochemical inhibition of the menin-KMT2A interaction loops in mixed-lineage leukemias
Names of Authors: M. A. Bello¹, O. R. Eze²
Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria
Abstract: Chromosomal translocations involving the lysine methyltransferase 2A (KMT2A) gene drive high-risk leukemic transformations characterized by poor clinical outcomes and limited response to intensive multi-agent regimens. This comprehensive review examines the molecular structural mechanics of the oncogenic KMT2A-fusion protein complex, detailing its mandatory dependence on the small-molecule cofactor menin to sustain high transcription levels of homeobox (HOXA) and MEIS1 target genes. This continuous up-regulation effectively blocks hematopoietic differentiation, locking mixed-lineage myeloblasts or lymphoblasts in proliferative loops. Evolving therapeutic models focus on blocking this binding site using highly selective, small-molecule menin inhibitors like revumenib (SNDX-5613) and ziftomenib. These inhibitors sit directly within the hydrophobic central pocket of menin, disrupting the KMT2A interaction, down-regulating HOXA machinery, and inducing rapid morphologic differentiation. However, secondary drug resistance point mutations within the menin binding pocket present ongoing challenges. This review details structural biomarkers, mutant variant tracking, and clinical combination schedules designed to optimize menin-inhibition and maximize survival outcomes in KMT2A-rearranged mixed-lineage leukemias.
Keywords: Mixed-lineage leukemia, KMT2A rearrangement, menin inhibitors, revumenib, differentiation block
Manuscript Timeline: Received: April 18, 2024; Revised: May 22, 2024; Accepted: June 10, 2024; Published: July 15, 2024