In conclusion, our study provides critical insights into the clinical implications of complex gene fusions and subclonal evolution in AML, offering a multilayer diagnostic strategy, highlighting therapeutic vulnerabilities in underexplored fusions like CCDC32/CBX3, emphasizing the prognostic significance of fusion variability in relapse risk, and demonstrating broader relevance through parallels with other malignancies, thus paving the way for personalized treatment strategies and advancing cancer biology of drug resistance. This evidence concerns the gene CBX3 and acute myeloid leukemia.