KMT2A Amplification in Mixed-Phenotype Acute Leukemia: Immunophenotyping, Cytogenomic Features, and Clinical Correlation

Context.—: Mixed-phenotype acute leukemia (MPAL) is a rare form of leukemia with a typically unfavorable prognosis. While KMT2A (lysine methyltransferase 2A) rearrangements resulting in gene fusions are common in MPAL, information on KMT2A amplification is lacking. Objective.—: To determine whether KMT2A-amplified MPAL correlates with complex karyotype, TP53 (tumor protein p53) aberration, and shortened survival, aiming to refine risk stratification for better patient management. Design.—: Flow cytometry, karyotyping, fluorescence in situ hybridization, single nucleotide polymorphism (SNP) microarray, and molecular approaches were used to characterize 3 MPAL cases with KMT2A amplification and clinical correlation. Results.—: All 3 cases exhibited B-lymphoid/myeloid phenotypes and highly complex karyotypes. Our analysis showed that KMT2A amplifications were intrachromosomal, appearing as homogeneously staining regions (hsr) in 2 cases. In patients 1 and 2, the hsr was located on ring chromosome 7 and chromosome 11, respectively. Interestingly, in patient 3, amplification was found on multiple marker chromosomes. TP53 abnormalities were observed in 2 cases. Single nucleotide polymorphism (SNP) microarray analysis of 1 case revealed oscillating copy number variations on chromosome 11, suggestive of chromoanasynthesis. The amplified region included cancer-related genes KMT2A and DDX6 (DEAD-box helicase 6). Conclusions.—: Findings from our study show that KMT2A-amplified MPAL is associated with complex karyotypes, TP53 abnormalities, and an inferior outcome. Our data may help refine MPAL risk stratification.