A Case of Cryptic CBFB::MYH11 Acute Myeloid Leukemia With Noncanonical Breakpoints Detected by Optical Genome Mapping

Accurate and timely detection of clinically relevant genetic abnormalities, such as CBFB::MYH11 or inversion(16) [inv(16)], is critical for the diagnosis and management of patients with acute myeloid leukemia (AML). Notably, CBFB::MYH11 is a disease-defining mutation in AML and is associated with a favorable prognosis. The current standard-of-care workup, which includes a combination of conventional G-banding karyotyping, fluorescence in situ hybridization (FISH), and/or reverse-transcriptase PCR, poses challenges in detecting variant CBFB::MYH11 translocations. High-resolution, genome-wide technologies capable of accurate and unbiased detection of chromosomal structural aberrations at the gene/exon level, such as optical genome mapping (OGM), will be helpful for the timely detection of clinically actionable abnormalities. This case report presents a patient initially diagnosed with therapy-related myelodysplastic syndrome (MDS) following cytotoxic therapy and treated with a hypomethylating agent, who later experienced progression to AML with CBFB::MYH11. Retrospective analysis of the initial diagnostic sample using OGM revealed a cryptic CBFB::MYH11 abnormality at the time of the first presentation. Furthermore, OGM enabled comprehensive characterization of this novel CBFB::MYH11 transcript with noncanonical breakpoints, which were not detected by standard molecular techniques. This case highlights a critical diagnostic blind spot in the detection of CBF::MYH11 AML, representing a missed opportunity to offer effective frontline therapy to a patient with potentially curable AML—an aberration not recognized by conventional karyotype or FISH at the time of initial diagnosis. The implementation of genome-wide technologies such as OGM as a first-tier diagnostic tool in clinical laboratories for the workup of MDS/AML is essential for detecting clinically impactful cryptic genomic alterations. The discovery of this novel alternate CBFB::MYH11 transcript with noncanonical breakpoints underscores a major limitation in current standard-of-care techniques, warranting further prospective studies to evaluate its clinical actionability in guiding personalized therapies.