A KMT2A mutation (formerly known as MLL1) is a genetic alteration in the KMT2A gene on chromosome 11q23, which is critical for regulating gene expression and blood cell development.
These mutations are primarily associated with aggressive types of leukemia, including Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL).
Types of KMT2A Alterations include:
Genetic Rearrangements (KMT2Ar): The most common form in leukemia, where KMT2A fuses with one of over 100 possible partner genes (like AFF1, MLLT1, or MLLT3).
Partial Tandem Duplications (KMT2A-PTD): Internal duplications within the gene itself, often seen in AML and associated with a poor prognosis.
Point Mutations (SNV): Rare short-variant mutations that can occur in various cancers.
Germline Mutations: Inherited mutations that cause Wiedemann-Steiner Syndrome, a condition characterized by intellectual disability and distinct physical features.
Clinical Significance:
Leukemias with KMT2A rearrangements typically have rapid onset, high relapse rates, and poor survival outcomes with an overall survival often below 25%.
Infant Leukemia: KMT2A rearrangements are found in approximately 80% of infant ALL cases.
Therapeutic Targets:
Treatments focus on inhibiting the Menin-KMT2A interaction.
The FDA-approved drug Revumenib (Revuforj) is used for relapsed or refractory acute leukemia with this specific translocation.