KMT2A

Overview

KMT2A (Lysine Methyltransferase 2A), formerly known as MLL (Mixed-Lineage Leukemia), encodes a histone methyltransferase that plays a critical role in early development and hematopoiesis. It is frequently rearranged in acute leukemias, particularly in infants, where it forms oncogenic fusion proteins with various partner genes.

Alterations observed in the corpus

  • Rearrangements / Fusions: 11q23 translocations involving KMT2A are the primary driver in infant MLL-rearranged ALL; these were present in 47 infants in the St. Jude cohort PMID:25730765.
  • Paucity of secondary mutations: The KMT2A rearrangement itself is considered a potent driver, as infant cases harbor exceptionally few additional somatic mutations PMID:25730765.
  • KMT2A is a chromatin-modifying gene with high prevalence of non-silent variants in metastatic UC (UC-GENOME cohort) PMID:36333289
  • KMT2A (MLL) alteration detected in prostate cancer WES cohort (Michigan, 112 tumors); KMT2A rearrangements link histone H3K4 methylation dysregulation to prostate cancer progression PMID:22722839
  • Recurrent missense mutation (Ile960Met) identified in SCLC (29 tumors, CLCGP WES/WGS); histone methyltransferase PMID:22941188
  • Chromatin-modifying gene recurrently altered in AML; fusion partners observed include MLLT3 (AF9) and MLLT10 (AF10); MLL-fused AML samples carried the fewest cooperating mutations of any subgroup PMID:23634996
  • Somatic mutation as part of the histone lysine methyltransferase KMT2A/KMT2C/KMT2E group, collectively altered in 16% of transitional cell carcinoma (BLCA) bladder tumors in a 99-sample WES cohort PMID:24121792
  • KMT2A is listed among recurrently mutated genes in the HCC WES landscape (n=1,289), part of the chromatin-modifier/epigenetic regulator gene set in hepatocellular carcinoma. PMID:24798001
  • KMT2A listed among additional candidate chromatin-remodeling drivers in PTC; 93 mutations across 57 epigenetic regulator genes in 80/402 (20.0%) tumors including KMT2A PMID:25417114
  • Chromatin-modifying gene mutated in UTUC; mutations common in both low- and high-grade tumors and concordant across spatial tumor components, suggesting early/clonal events PMID:26278805
  • KMT2A, together with KMT2C, KMT2D, and SETD2, are histone methyltransferases mutated collectively in 24% of ATC vs 7% of PDTC (P = 0.02); HMT enrichment in ATC is cited as rationale for chromatin-targeted therapy PMID:26878173
  • KMT2A PTD is a chromatin regulator defining the chromatin-spliceosome AML subgroup (18%, n=275); KMT2A PTD × FLT3 TKD co-occurrence (n=10) was strongly adverse (q=0.008); KMT2A fusions present in 3% (n=44) of 1540 AML patients with multiple partners — MLLT3-KMT2A t(9;11) appears favorable relative to other KMT2A fusions PMID:27276561
  • Recurrently mutated in unclassified renal cell carcinoma (uRCC, n=62 MSKCC cohort); KMT2A/C/D combined account for 16% of cases in the chromatin-modulator group; KMT2A-mutated cases cluster in the chromatin/DNA-damage regulator subgroup associated with intermediate clinical outcome. PMID:27713405
  • KMT2A–AFF1 (MLL-AFF1) fusion identified in pediatric AML as a DOT1L-inhibitor target in comprehensive clinical genomic sequencing PMID:28007021.
  • Newly recognized SMG in MIBC (n=412, TCGA BLCA 2017), mutated in 11%; part of the pervasive chromatin-modifier mutation cluster with predominantly inactivating mutations. PMID:28988769

Cancer types (linked)

  • BLLKMT2A: Characterized by an extremely low somatic mutation burden (mean 1.3 per case) and frequent (47%) kinase/PI3K/RAS signaling mutations PMID:25730765.

Co-occurrence and mutual exclusivity

  • FLT3: Activating mutations in FLT3 found in 19% of infant MLL-R cases; often sub-clonal PMID:25730765.
  • KRAS / NRAS: Activating mutations in the RAS pathway found in approximately 28% of cases combined PMID:25730765.

Therapeutic relevance

  • The sub-clonal nature of signaling pathway mutations at relapse suggests that the founder clone persists through standard therapy, highlighting the need for treatments targeting the MLL fusion itself or its essential downstream effectors PMID:25730765.

Open questions

  • The necessity of sub-clonal kinase/PI3K/RAS mutations for leukemogenesis versus promoting clonal expansion remains to be fully elucidated PMID:25730765.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36333289

This page was processed by crosslinker on 2026-05-14. - PMID:22722839

This page was processed by crosslinker on 2026-05-14. - PMID:22941188

This page was processed by crosslinker on 2026-05-14. - PMID:23634996

This page was processed by crosslinker on 2026-05-14. - PMID:24121792

This page was processed by crosslinker on 2026-05-14. - PMID:24798001

This page was processed by crosslinker on 2026-05-14. - PMID:25417114

This page was processed by crosslinker on 2026-05-14. - PMID:26278805

This page was processed by crosslinker on 2026-05-14. - PMID:26878173

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15. - PMID:27713405

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

This page was processed by entity-page-writer on 2026-05-15. - PMID:28988769

This page was processed by entity-page-writer on 2026-05-15.