KMT2A rearrangements

KMT2A rearrangements are chromosomal translocations involving the KMT2A gene that create fusion proteins and occur in certain blood cancers such as acute lymphoblastic leukemia (ALL)[1] and acute myeloid leukemia (AML).[2] They also occur less commonly in mixed-phenotype acute leukemia as well as myeloid sarcomas, soft tissue sarcomas, and thymomas.

KMT2A fusion proteins can inhibit cellular differentiation and promote leukemogenesis.[3]

Leukemia

The effect of KMT2A rearrangements on prognosis varies by leukemia type, age, and protein fusion partner. In AML, some fusions carry high risk whereas others have outcomes similar to other AML subtypes.[1] Cancers harboring KMT2A fusions can be targeted with drugs such as menin inhibitors.[3][4][5] Revumenib is an approved memin inhibitor drug used to treat relapsed or refractory acute leukemia.[6]

Other cancers

KMT2A rearrangements have been found in myeloid sarcoma (a solid collection of leukemic cells) as KMT2A-MLLT3 fusions.[7] KMT2A rearrangements have been detected in 0.2% of soft tissue sarcomas, most often as YAP1 and less commonly as VIM fusions.[8] Finally KMT2A–MAML2 gene fusions have also been identified in aggressive subtypes of thymoma.[9]

Mechanism of action

KMT2A fusion proteins acquire activities from the fused partner protein. These capacities include either the ability to recruit DOT1L (a histone H3 lysine 79 methyltransferase) or components of the super elongation complex. These added capacities allow sustained transcription of specific genes that promote cell survival and block cellular differentiation.[10]

Menin interacts both with wild-type KMT2A, and KMT2A fusion proteins and menin inhibitors block the binding of menin to both wild-type KMT2A and KMT2A fusion proteins.[11]

References

  1. 1 2 PDQ Pediatric Treatment Editorial Board (2025). "Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®): Health Professional Version". PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US). PMID 26389206.
  2. ↑ PDQ Pediatric Treatment Editorial Board (2025). "Childhood Acute Myeloid Leukemia Treatment (PDQ®): Health Professional Version". PDQ Cancer Information Summaries. Bethesda (MD): National Cancer Institute (US). PMID 26389454.
  3. 1 2 Guarnera L, D'Addona M, Bravo-Perez C, Visconte V (August 2024). "KMT2A Rearrangements in Leukemias: Molecular Aspects and Therapeutic Perspectives". International Journal of Molecular Sciences. 25 (16): 9023. doi:10.3390/ijms25169023. PMC 11354696. PMID 39201709.
  4. ↑ Peters DT, Hatfield J, Reese M, Zeidner JF (March 2026). "Menin Inhibitors: A New Era of Targeted Therapies in Acute Myeloid Leukemia". Current Treatment Options in Oncology. 27 (1) 15. doi:10.1007/s11864-025-01378-6. PMID 41843240.
  5. ↑ Watts J, Madarang E, Cierpicki T, Grembecka J (August 2026). "Menin inhibitors as a treatment for acute leukemia: from bench to the clinic". Blood Neoplasia. 3 (3) 100253. doi:10.1016/j.bneo.2026.100253. PMC 13382185. PMID 42519171.
  6. ↑ Center for Drug Evaluation and Research (15 November 2024). "FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation". U.S. Food and Drug Administration. Food and Drug Administration. Retrieved 5 August 2026.
  7. ↑ Diamantidis MD (October 2024). "Myeloid Sarcoma: Novel Advances Regarding Molecular Pathogenesis, Presentation and Therapeutic Options". Journal of Clinical Medicine. 13 (20). doi:10.3390/jcm13206154. PMC 11509401. PMID 39458104.
  8. ↑ Folpe AL (January 2022). "'I Can't Keep Up!': an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours". Histopathology. 80 (1): 54–75. doi:10.1111/his.14460. PMID 34958510.
  9. ↑ Massoth LR, Hung YP, Dias-Santagata D, Onozato M, Shah N, Severson E, et al. (2020). "Pan-Cancer Landscape Analysis Reveals Recurrent KMT2A-MAML2 Gene Fusion in Aggressive Histologic Subtypes of Thymoma". JCO Precision Oncology. 4. doi:10.1200/PO.19.00288. PMC 7446345. PMID 32923872.
  10. ↑ Ogino J, Dou Y (September 2024). "Histone methyltransferase KMT2A: Developmental regulation to oncogenic transformation". The Journal of Biological Chemistry. 300 (10) 107791. doi:10.1016/j.jbc.2024.107791. PMC 11736124. PMID 39303915.
  11. ↑ "REVUFORJ (revumenib) tablets, for oral use: Prescribing information" (PDF). U.S. Food and Drug Administration. 15 November 2024. Retrieved 6 August 2026.
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