A novel H2A-A127 variant is associated with human cancer and enhances tumor-related phenotypes in

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 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. 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.