Abstract
BACKGROUND: Gene fusions define leukemia subtypes, predicting prognosis and guiding treatment. The classical t(8;21)(q22;q22) translocation results in the RUNX1::RUNX1T1 fusion, characteristic of favorable risk acute myeloid leukemia (AML). To date, more than 21 genes have been identified as partners of RUNX1, each associated with a distinct impact on behavior and outcome. Traditional cytogenetic and molecular techniques often fail to detect cryptic or complex rearrangements, resulting in suboptimal risk assessment. This is a relapsed case of t(8;21) AML involving the rare partner gene PLAG1, identified by optical genome mapping. A review of published cases highlights the distinct prognosis of this fusion. CASE PRESENTATION: A 71-year-old female previously diagnosed with AML, developed a cytogenetic clone with t(8;21)(q?12-13;q22) at relapse. FISH showed RUNX1 rearrangement, without RUNX1T1 involvement. RT-MLPA and Next Generation Sequencing showed KMT2A partial tandem duplication and pathogenic variants in ASXL1, PHF6, RUNX1 and SF3B1. Customized FISH probes identified the breakpoint within the region spanning PLAG1, confirmed as a translocation partner by OGM. The patient showed disease refractoriness despite multiple lines of chemotherapy and died 17 months after diagnosis. DISCUSSION AND CONCLUSIONS: PLAG1 is a rare translocation partner of RUNX1 in AML, mistaken for classical t(8;21) on conventional karyotyping. The rare reported cases of PLAG1::RUNX1 suggest a distinctly poor prognosis, highlighting the importance of accurate diagnosis and the role of OGM in our practice.