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

Classical acute promyelocytic leukemia (APL) is defined by the presence of the PML::RARA 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 PML::RARA, while targeted sequencing revealed mutations in DNMT3A and DHX15. 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 KMT2C::CREB3L2 fusion and a rare KDM6A mutation. Notably, transcriptomic analysis demonstrated marked overexpression of RARA and RXRA. 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 PML::RARA 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 PML::RARA rearrangement, with important therapeutic implications. The online version contains supplementary material available at 10.1007/s00277-026-06983-5.