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Characterizing KMT2A Rearrangement in Acute Myeloid Leukemia: A Comprehensive Genomic Study
by
, , , , and
Osama Batayneh
1,*
,
Mahmoudreza Moein
2,
Nour Sabiha Naji
2,
Ansy Patel
2,
Anupa R. Mandava
1,
Alexandra Goodman
3,
Jeffrey S. Ross
2,4,
Caleb Ho
4,
Chelsea Marcus
4,
Zheng Zhou
5,
Gillian Kupakuwana-Suk
1,
Teresa Gentile
1 and
Krishna B. Ghimire
1 1
Department of Medicine, Division of Hematology/Oncology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
2
Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA
3
Novant Health Zimmer Cancer Institute, Wilmington, NC 28401, USA
4
Foundation Medicine, Cambridge, MA 02141, USA
5
Division of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA
*
Author to whom correspondence should be addressed.
Cancers 2026, 18(1), 161; https://doi.org/10.3390/cancers18010161
Submission received: 1 December 2025
/
Revised: 28 December 2025
/
Accepted: 29 December 2025
/
Published: 2 January 2026
(This article belongs to the Special Issue Lymphoid and Myeloid Leukemias—Current Progress in Biology and Treatment)
Simple Summary
FLT3 and IDH2 mutations are more commonly seen in KMT2A-rearranged acute myeloid leukemia (KMT2Ar AML), whereas NPM1, TP53, and myelodysplasia-related mutations are more commonly seen in KMT2A wild-type AML (KMT2Awt). This genomic landscape study highlights significant genomic differences between KMT2A-arranged and wild-type AML, which may enrich our understanding of the molecular profile and associations between mutations in AML.
Abstract
Background: The KMT2A (MLL1) gene is altered in a variety of hematological malignancies and solid tumors. KMT2A-rearranged (KMT2Ar) AML represents a distinct subtype associated with poor outcomes and high relapse rate despite initial responsiveness to chemotherapy. Methods: A total of 3863 cases of AML peripheral blood samples were analyzed using the FoundationOne Heme combined comprehensive hybrid capture-based DNA and RNA sequencing assay. Results: Of the 3863 AML cases, 521 (13.4%) featured genomic alterations (GAs) in the KMT2A gene, 99.1% of which were large rearrangements (KMT2Ar). A total of 56.9% were males with a median age of 62 years. Of the KMT2Ar cases, there were 43.1% KMT2A duplications, 52.7% fusions, and 4.2% not otherwise specified rearrangements. A total of 0.9% of the KMT2A-altered AML cases were short variant mutations. There were no KMT2A (0%) amplifications or deletions. KMT2Ar cases were associated with increased GA frequencies in FLT3 (27.3% vs. 19.8%; p = 0.0002), KRAS (17.2% vs. 7.8%; p < 0.0001) (overall; 1.1% KRAS G12C), and IDH2 (16.0% vs. 10.4%; p < 0.0001), while KMT2A wild-type AML (KMT2Awt) had significantly increased GA frequencies in RUNX1 (20.7% vs. 15.8%; p = 0.0081), ASXL1 (16.6% vs. 10.5%; p = 0.0003), and TET2 (16.4% vs. 10.1%; p = 0.0002), NPM1 (17.5% vs. 0.2%; p < 0.0001), and TP53 (17.8% vs. 7.9%; p < 0.0001). Conclusions: KMT2A rearrangements are common in AML (13.4% of cases featured KMT2Ar). A total of 99.1% of alterations in KMT2A are large rearrangements, with fusions being the most commonly observed alteration (52.7% of total rearrangements). No amplifications or deletions were seen. This genomic landscape study highlights significant genomic differences between KMT2Ar and KMT2Awt AML patients, which may enrich our understanding of the molecular profile and clusters of mutations in AML.
