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Acute Myeloid Leukemia in Children: Pathobiology – KMT2A Gene Rearrangements

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P1015-1016

2026-10-29

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The KMT2A gene, located on chromosome 11 band q23, encodes the MLL histone methylase. Upon proteolytic cleavage, it is part of a multiprotein complex involved in chromatin remodeling. Knockout of KMT2A inhibits myeloid and lymphoid differentiation and rapidly leads to bone marrow failure in mice. These results suggest that the MLL protein is not only required for definitive hematopoiesis but is also required for maintenance of HSCs in postnatal hematopoiesis.

Chromosomal translocations involving the KMT2A gene are associated with both AML and ALL leukemias. There are more than 100 different fusion partners identified, although nine specific genes account for more than 90% of the fusion events. KMT2A rearrangements are found in 60% to 70% of infants with leukemia (predominantly KMT2A/AFF1), regardless of immunophenotype, but are less common in older children and adults. The distribution of translocation partners varies depending on the age of the patient and the immunophenotype of leukemia, with KMT2A/MLLT10 being more frequent in infant and pediatric AML. The majority of active KMT2A fusion proteins contain the N-terminus of KMT2A and the C-terminus of the fusion partner gene, while the function of reciprocal fusion proteins harboring the KMT2A C-terminus are not well understood. The prognostic significance of KMT2A mutations is often dictated by the fusion partner and can range from favorable to highly unfavorable. Next-generation sequencing of KMT2A-rearranged leukemias demonstrated a paucity of cooperating mutations, although approximately 50% carry an activating tyrosine kinase mutation.19 However, those mutations are often absent at relapse, confirming they may represent secondary events in irrelevant subclones. KMT2A fusion genes alone are sufficient for leukemogenesis, and the targeting of cooperating mutations may not result in a therapeutic benefit.