KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives

• Published in: International journal of molecular sciences Vol. 25; no. 16; p. 9023
• Main Authors: Guarnera, Luca, D'Addona, Matteo, Bravo-Perez, Carlos, Visconte, Valeria
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20-08-2024; MDPI
• Subjects: Adults; Gene Rearrangement; Genes; Hematopoietic Stem Cell Transplantation; Histone-Lysine N-Methyltransferase - genetics; Humans; KMT2A rearrangements; Leukemia; Leukemia - genetics; Leukemia - therapy; Medical prognosis; molecular lesions; Mutation; Myeloid-Lymphoid Leukemia Protein - genetics; Review; therapies; Translocation, Genetic; Transplants & implants; Tumors; KMT2A rearrangements; therapies; molecular lesions
• ISSN: 1661-6596; 1422-0067; 1422-0067
• DOI: 10.3390/ijms25169023

(alias: mixed-lineage leukemia [
]) gene mapping on chromosome 11q23 encodes the lysine-specific histone N-methyltransferase 2A and promotes transcription by inducing an open chromatin conformation. Numerous genomic breakpoints within the
gene have been reported in young children and adults with hematologic disorders and are present in up to 10% of acute leukemias. These rearrangements describe distinct features and worse prognosis depending on the fusion partner, characterized by chemotherapy resistance and high rates of relapse, with a progression-free survival of 30-40% and overall survival below 25%. Less intensive regimens are used in pediatric patients, while new combination therapies and targeted immunotherapeutic agents are being explored in adults. Beneficial therapeutic effects, and even cure, can be reached with hematopoietic stem cell transplantation, mainly in young children with dismal molecular lesions; however, delayed related toxicities represent a concern. Herein, we summarize the translocation partner genes and partial tandem duplications of the
gene, their molecular impact, clinical aspects, and novel targeted therapies.