Identification of an Elusive Fusion Variant in Acute Megakaryoblastic Leukemia by Whole Genome Sequencing.

Advancements in genomic profiling have significantly improved the classification and treatment strategies for acute myeloid leukemia (AML). However, widely utilized molecular diagnostic techniques, including targeted gene panels, are often insufficient for detecting complex structural variants, cryptic fusions, and poorly characterized driver mutations. Here, we present the case of a 15-month-old female with pediatric acute megakaryoblastic leukemia (AMKL) who exhibited an atypical clinical presentation. Initial imaging revealed expansile lesions in the pelvic bones and vertebral bodies, prompting suspicion of malignancy. Conventional diagnostics, including immunohistochemistry and targeted sequencing, failed to identify a definitive oncogenic driver. Whole genome sequencing (WGS) identified a fusion, leading to a revised AMKL diagnosis with a RAM immunophenotype. The patient underwent induction chemotherapy with cytarabine and mitoxantrone, followed by salvage therapy with venetoclax and azacitidine, resulting in morphologic remission. Subsequent haploidentical hematopoietic stem cell transplantation achieved remission, with ongoing hematologic recovery. This case underscores the limitations of conventional molecular assays in detecting cryptic fusions and highlights the critical role of comprehensive genomic profiling in refining subclassification and optimizing therapeutic strategies in pediatric AML.