Revealing the Hidden: Microarray Detection of KMT2A Partial Tandem Duplication in Myeloid Malignancies

Summary: Rearrangements of the KMT2A gene, located on chromosome 11q23.3, are common in myeloid or mixed lineage hematological malignancies and are generally associated with poor prognosis. KMT2A alterations range from translocations to amplifications and partial tandem duplications (PTDs). Detection of KMT2A PTDs is complicated as they are cytogenetically cryptic and not detectable by conventional karyotyping or fluorescence in situ hybridization (FISH). Chromosomal microarray analysis (CMA) is a high-resolution tool that enables detection of submicroscopic genomic alterations including KMT2A PTDs. In this study, we examined the utility of microarray in detection of KMT2A PTDs among patients tested with suspicion for myeloid malignancies. Retrospective studies were performed on microarray, FISH and karyotype results from a total of 4,207 patients tested at the UPMC Cytogenetics Laboratories during 2019-2024. We identified 47 patients (1.1%) with KMT2A PTD based on microarray findings. The affected patients ranged in age from 40-87 years (mean age: 72). Duplicated regions commonly included exons 2-15 of KMT2A gene, with exons 2-10 most frequently involved. PTD sizes ranged from 6-46.4 kb (mean: 19 kb). Additional chromosomal aberrations were detected by microarray in 30 of 47 patients (64%). Abnormal karyotype was observed in 19/47 patients (40.4%), none of which revealed KMT2A gain on chromosome 11. In total, 10/47 patients (21%) had abnormal FISH results, including 4 that showed an extra signal for KMT2A. Molecular analysis revealed pathogenic variants in 36/47 patients (76%) involving FLT3, TET2, IDH1/IDH2, ASXL1, DNMT3A, SRSF2, RUNX1, STAG2, and U2AF1. Our findings highlight the critical role of microarray in detecting KMT2A-PTDs with critical prognostic implications. Microarray analysis integration into the diagnostic workup of myeloid malignancies provides high-resolution detection, improves risk stratification, and informs treatment decisions. Michaelia Austin, Rachel Kirsch, Lynn Sniezek, Maria Fletcher, Angela Martin, Yinghong Pan, and Mahmoud Aarabi