Chromoplexy and FNDC3B::RARB fusion: deciphering a rare case of PML::RARA-negative APL

A 30-year-old man was admitted to the hospital with a 1-week history of asthenia and febrile angina. Blood tests revealed pancytopenia and 25% immature myeloid cells, but no blast cells. Coagulation tests were normal. Bone marrow aspiration with 93% blasts and numerous clustered Auer rods was highly suggestive of acute promyelocytic leukemia (APL) (panel A: May-Grünwald Giemsa staining, original magnification ×100). Flow cytometry revealed high side scatter with cMPO⁺, CD33⁺, CD117⁺, CD34⁻ (consistent with promyelocytes), but atypical HLA-DR⁺. PML::RARA fast fluorescence in situ hybridization (FISH) was negative. Cytogenetics revealed loss of chromosome Y and a complex rearrangement involving chromosomes 3 and 7, with a pericentric inversion on chromosome 3 affecting 3p24, which carries the RARB gene (panel B). Due to the lack of RARB-specific FISH probes, further investigation was conducted using optical genome mapping, which identified a chromoplexy involving a 9-partner translocation, resulting in an FNDC3B::RARB fusion (panel C), confirmed by reverse transcription polymerase chain reaction (panel D).

As the patient did not develop a differentiation syndrome with all-trans retinoic acid alone, an induction chemotherapy was added. He achieved complete remission with minimal residual disease below 0.1% by flow cytometry after 2 cycles. However, all-trans retinoic acid’s specific contribution to this outcome remains uncertain. The patient is awaiting allogeneic transplantation. RAR rearrangements beyond RARA occur in ∼2% of APL cases. RARA-negative APLs are typically retinoid-resistant, and their optimal treatment remains undefined. Advanced genetic techniques, such as optical genome mapping or transcriptomics, are crucial to avoid overlooking these variants.

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