Chromosomal BCR-ABL1 fusions are the defining molecular lesions of chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia, and are rarely observed in acute myeloid leukemia. Their detection have transformed treatment paradigms by enabling effective use of specific tyrosine kinase inhibitors (TKIs). Although many BCR-ABL1 rearrangements are identified by standard cytogenetics, a clinically relevant subset is cryptic and can escape detection. High-depth RNA sequencing assays have improved our capacity to detect expressed fusion transcripts. Here, we introduce two myeloid cases in which cryptic BCR-ABL1 rearrangements and precise breakpoints detection required an integrated molecular approach: we describe the initial diagnostic pitfalls, detail the downstream therapeutic and prognostic implications and offer practical recommendations for integrating targeted sequencing and cytogenetics into routine practice. In the first case, a patient initially diagnosed with a myelodysplastic/myeloproliferative neoplasm was reclassified as CML following the discovery of a cryptic e13a2 BCR-ABL1 rearrangement, enabling effective TKI treatment. In the second case, a previously undetected BCR-ABL1 fusion was identified in a relapsed AML patient, along with additional molecular lesions, underscoring the aggressive nature of the disease. Our findings support a systematic, multimodal screening strategy in patients with atypical presentations to ensure the timely detection of clinically actionable fusion events.
Keywords: BCR-ABL1; NGS; acute myeloid leukemia; diagnostics; fusions.