Unveiling Cryptic BCR-ABL1 Rearrangements: Diagnostic Challenges and Clinical Impact in Myeloid Malignancies

Chromosomal <i>BCR-ABL1</i> 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 <i>BCR-ABL1</i> 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 <i>BCR-ABL1</i> 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 <i>BCR</i>-<i>ABL1</i> rearrangement, enabling effective TKI treatment. In the second case, a previously undetected <i>BCR</i>-<i>ABL1</i> 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.