The silent players: Atypical BCR‑ABL isoforms as biomarkers and therapeutic hurdles in CML pathogenesis (Review).

Abstract

Chronic myeloid leukemia (CML) is a hematological malignancy driven by diverse genetic aberrations, with the Philadelphia chromosome and its resultant BCR‑ABL1 fusion gene constituting key pathogenic drivers. Atypical BCR‑ABL1 fusion transcripts have distinctive structural and functional properties. Structural divergence in these variants leads to functional alterations of encoded oncoproteins, potentially influencing disease progression and therapeutic responsiveness. Conventional diagnostic modalities, including reverse transcription‑PCR and fluorescence in situ hybridization, may fail to detect rare variants, necessitating complementary high‑sensitivity techniques such as next‑generation sequencing). Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, remain cornerstone treatments; however, marked inter‑variant heterogeneity in TKI responsiveness is observed: Patients harboring e13a3/e14a3 transcripts generally show favorable prognoses, while those with e1a3/e6a2 variants demonstrate an increased risk of relapse and/or TKI resistance, often requiring multimodal strategies combining chemotherapy or allogeneic hematopoietic stem cell transplantation. Although Chimeric Antigen Receptor)‑T cell therapy has shown promise in treating (Philadelphia chromosome‑positive B‑cell Acute Lymphoblastic Leukemia, its application in CML, particularly in variants such as e1a3 or e6a2, is not currently recommended as a first‑line treatment. Despite advances in elucidating the clinical implications of fusion gene heterogeneity in leukemogenesis, the prognostic value of atypical BCR‑ABL1 isoforms requires further validation through multicenter studies with extended cohorts. This review aimed to summarize cases of atypical fusion genes in CML, with analysis of clinical characteristics, therapeutic interventions, and prognostic outcomes, to provide clinicians with enhanced reference material for improved patient management.