Advances in CBFA2T3::GLIS2 Fusion Gene in Pediatric Acute Myeloid Leukemia: from Molecular Mechanisms to Targeted Therapeutic Strategies

Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy in children, with molecular alterations playing critical roles in disease development and therapeutic responses. The CBFA2T3::GLIS2 (C/G) is the most frequent genetic alteration identified in non-Down syndrome acute megakaryoblastic leukemia (AMKL) and results from a cryptic inversion involving the subtelomeric region of chromosome 16. Multiple chimeric transcripts can be generated depending on the breakpoint location, with CBFA2T3-ex11/GLIS2-ex3 being the predominant transcript. This fusion gene is associated with chemotherapy resistance and an unfavorable clinical outcome. Although initially identified in AMKL, it has also been detected in several cytogenetically normal AML subtypes, including M0, M1, M2, M4, and M5. However, the molecular mechanisms underlying C/G fusion-driven leukemogenesis remain incompletely characterized. This review provides an overview of the pathogenic mechanisms, emerging therapeutic strategies, and clinical challenges associated with C/G-positive pediatric AML.