# Characterizing KMT2A Rearrangement in Acute Myeloid Leukemia: A Comprehensive Genomic Study

## TL;DR

This study shows that KMT2A gene rearrangements in AML are linked to specific mutations like FLT3 and IDH2, while wild-type KMT2A is associated with other mutations like NPM1 and TP53.

## Contribution

The study identifies distinct genomic profiles between KMT2A-rearranged and wild-type AML, offering new insights into mutation clusters in the disease.

## Key findings

- KMT2A-rearranged AML is associated with higher frequencies of FLT3, KRAS, and IDH2 mutations.
- KMT2A wild-type AML shows increased frequencies of NPM1, TP53, and myelodysplasia-related mutations.
- 99.1% of KMT2A alterations are large rearrangements, with fusions being the most common.

## Abstract

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.

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.