Complex genetic structural aberrations revealed by optical genome mapping in a case of APL-like morphology.

We present a detailed cytogenomic analysis from a patient with suspected acute promyelocytic leukemia (APL), based on morphological and immunophenotypic characteristics. Initial testing with fluorescence in situ hybridization (FISH) and chromosome analysis was negative for the canonical PML::RARA and other RARA partners translocations. Polymerase chain reaction (PCR) did not detect PML::RARA transcripts. However, chromosome analysis results revealed loss of 5q and 17p, as well as the presence of double minutes (dmin). To further assess the involvement of other retinoic acid receptor (RAR) partners, such as RARB and RARG, and to elucidate the origin of the dmin, we conducted genome-wide structural variant analysis (gwSVA) using optical genome mapping (OGM) as part of a research and confirmatory follow-up. Using gwSVA, we identified the double minutes to be of MYC origin, with approximately 44 copies. Additionally, gwSVA revealed a loss of TP53, along with polyploidy showing loss of chromosomes 1, 2, 8, 9 (including CDKN2A), 10, 11, 15 and gains of chromosomes 3, 6, and 7 indicating distinct clonal events in a diagnostic and follow up bone marrow. Next generation sequencing (NGS) with an exome-based heme targeted panel identified a Tier I deleterious TP53 single nucleotide variant (p.S241C). The follow-up bone marrow analyzed with gwSVA, four months post-induction therapy, showed a reduction in number of cells exhibiting MYC amplification. This study provides a rare instance of a TP53 positive case with APL-like bone marrow morphology, no RARA rearrangement, and MYC amplification. It further lends evidence towards comprehensive cytogenomic and molecular analyses for accurate risk stratification and subsequent disease tracking.