Concomitant Clonal :: and Fusions in a Case of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) with :: fusion and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are genetically defined and typically mutually exclusive entities. We report a unique case of AML harboring two clonal, transcriptionally active class-defining fusions: :: and ::. A 61-year-old woman presented with leukocytosis with neutrophilia, eosinophilia, and monocytosis; circulating blasts; and a markedly hypercellular marrow. Cytogenetic analysis revealed inv(16)(p13.1q22) and t(3;5)(p21;q32) in all 20 metaphases, and RNA sequencing confirmed expression of both :: and :: fusions. In addition, an oncogenic frameshift variant was identified. Hematopathologic findings were largely consistent with AML with :: fusion but exhibited features reminiscent of -rearranged MLN-TK. The patient achieved complete remission following the standard 7 + 3 induction chemotherapy regimen for AML with gemtuzumab ozogamicin. This case illustrates the diagnostic challenges posed by concomitant class-defining alterations in hematologic neoplasms and underscores the importance of integrated genomic assessment.