PML::RARA-negative APL-mimicking AML with a novel KMT2C::CREB3L2 fusion and RARA/RXRA-mediated sensitivity to all-trans retinoic acid.

[UNLABELLED] Classical acute promyelocytic leukemia (APL) is defined by the presence of the fusion; however, a subset of acute myeloid leukemia (AML) cases presents with morphological and clinical features highly suggestive of APL despite lacking this canonical rearrangement, creating diagnostic and therapeutic dilemmas. We report a 27-year-old woman initially diagnosed with AML characterized by myeloid sarcoma and a predominance of promyelocytes (44%) in the bone marrow. Fluorescence in situ hybridization and RNA sequencing failed to detect , while targeted sequencing revealed mutations in and . Although complete remission was achieved after induction therapy, the response to IA and subsequent CHA chemotherapy regimens was suboptimal. Two years later, the patient relapsed with severe coagulopathy and a marked increase in promyelocytes (71%). Comprehensive genomic re-evaluation at relapse identified a novel fusion and a rare mutation. Notably, transcriptomic analysis demonstrated marked overexpression of and . Based on these molecular findings, treatment with all-trans retinoic acid combined with intermediate-dose cytarabine was initiated, leading to rapid clinical improvement and achievement of complete remission. This case describes a rare AML entity that closely recapitulates the clinical and molecular features of APL in the absence of and suggests that activation of retinoic acid–responsive pathways, potentially mediated by RARA/RXRA overexpression and novel gene fusions, can occur independently of the canonical rearrangement, with important therapeutic implications.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s00277-026-06983-5.