A novel H2A-A127 variant is associated with human cancer and enhances tumor-related phenotypes in Drosophila melanogaster models
Introduction Acute Myeloid Leukemia (AML) is characterized by genetic and epigenetic dysregulation in myeloid progenitor cells. Histone H3 mutations disrupt chromatin and transcription, contributing to disease, but identifying mutations in histone genes is challenging due to sequence duplication. In particular, histone H2A genes H2AC18 and H2AC19, which share identical sequences, have been largely overlooked. Methods Cancer genomic datasets were interrogated to identify novel variants, and in vivo functional assays were conducted using Drosophila melanogaster tumor models. Results a recurrent Alanine to Valine substitution at position 127 (H2A-A127V) was identified in AML and also found in solid tumors, suggesting a broader cancer association. Using a Drosophila melanogaster model, H2A-A127V was shown to promote eye tumor phenotypes and, in the eyeful tumor model, intensified tissue overgrowth. The variant also interacts with the Enhancer of zeste (E(z)), a PRC2 complex member. E(z) downregulation in the presence of H2A-A127V enhanced ectopic growth, suggesting PRC2’s role in disease progression. Analysis of the 1000 Genomes Project revealed that H2A-A127V is an uncommon polymorphism (1.44%), potentially predisposing carriers to cancer. Discussion These findings uncover a novel cancer-associated histone variant and emphasize the need to consider duplicated histone genes in mutation analyses to better understand cancer development.