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KMT2A AML Pathogenesis and Presentation
Panelists explain that KMT2A-rearranged acute myeloid leukemia (AML) is an aggressive, molecularly distinct leukemia subtype marked by menin-dependent transcriptional dysregulation, poor response to standard therapy, diagnostic challenges, and high relapse risk—underscoring the urgency of RNA-based diagnostics, early transplant consideration, and emerging menin-targeted treatments to improve outcomes.
KMT2A-rearranged AML is a biologically and clinically distinct subtype of leukemia, driven by alterations in the KMT2A gene, a large methyltransferase critical in embryonic development and hematopoiesis. Rearrangements involving KMT2A, formerly known as MLL, lead to the fusion of its N-terminus with one of many potential partner genes—over 50 have been identified—which disrupts transcriptional regulation. This dysregulation enhances expression of genes in the HOXA cluster and MEIS1, pathways central to leukemogenesis. A key molecular feature of these fusions is their conserved interaction with menin, a protein essential for leukemic cell survival. This interaction has become a promising therapeutic target, with menin inhibitors showing potential to induce differentiation and apoptosis in leukemic cells.
Clinically, KMT2A-rearranged AML presents a unique and aggressive profile. Patients often show signs of hyperleukocytosis, extramedullary involvement, and bleeding complications. Diagnostically, these cases can be challenging because the rearrangements may not be detectable with standard cytogenetic tools such as karyotyping or fluorescence in situ hybridization. In such scenarios, RNA sequencing is required to confirm the diagnosis. Treatment responses are typically poor; patients frequently exhibit resistance to standard induction chemotherapy or relapse shortly after initial remission. As a result, clinicians often aim to move rapidly toward allogeneic stem cell transplantation when feasible, given the disease’s aggressive behavior and poor outcomes with conventional therapy.
From a patient perspective, this subtype can be especially difficult to understand and process. Although AML itself is already a high-stakes diagnosis, the added complexity and rarity of KMT2A rearrangements often require significant education and support. The urgency in treatment, the diagnostic complexity, and the evolving therapeutic landscape all underscore the need for personalized care strategies and continued research to improve outcomes.
