Optical Genome Mapping Reveals Complex and Cryptic Rearrangement Involving PML::RARA Fusion in Acute Promyelocytic Leukemia.

Abstract

Background/objectives: Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML), characterized by the hallmark translocation t(15;17) resulting in a PML::RARA fusion. Once diagnosed, APL is now considered to be one of the most treatable forms of AML. However, without early detection and treatment, the disease is associated with rapid deterioration and lethal side effects. Methods: We describe a case of diagnostic APL presenting with a normal karyotype, normal RARA break-apart FISH, and unclear, atypical PML/RARA FISH findings. We used optical genome mapping (OGM) to characterize this atypical PML/RARA fusion. Results: OGM allowed for detection of a PML::RARA fusion resulting from a cryptic and complex insertion of PML::RARA into RARA on 17q21.2 whereby a segment of 15q24.1 was inserted into the 17q21.2. The recipient breakpoint of the insertion was at intron 2 of the RARA gene and the donor breakpoint of the insertion was at exon 5/intron 6 of the PML gene. Conclusions: This is the first report of an insertional PML::RARA fusion into the RARA gene on 17q detected by OGM. OGM has demonstrated its utility in a clinical cytogenetics environment, allowing for clearer characterization and diagnosis of various neoplasms.