Molecular Characterization of <italic>MECOM</italic> Rearrangements in Two Cases with Myelodysplastic Syndrome and t(2;3)(p23;q26.2).

[INTRODUCTION] MECOM rearrangements are frequently observed in myeloid neoplasms and associated with poor prognosis. Among the genomic alterations leading to MECOM rearrangements, t(2;3)(p13∼p25;q26.2) accounts for approximately 13% of reported cases. However, the precise DNA breakpoints of this translocation have not been previously reported, nor has the mechanism by which it alters MECOM expression been fully elucidated. In this report, we describe two cases with myelodysplastic syndromes (MDS) and t(2;3)(p23;q26.2). Our genomic characterization of these two t(2;3) translocations provided insights into the molecular mechanism of MECOM activation.

[CASE PRESENTATION] Case 1 is a 44-year-old female who presented with new anemia and thrombocytopenia. She was treated with azacitidine. After two allogeneic stem cell transplants, her disease relapsed with rapid progression to acute myeloid leukemia (AML). The patient passed away 1 year after progression to AML and 8 years after initial diagnosis. Case 2 is a 75-year-old female who was incidentally found to have macrocytic anemia with rare circulating blasts. She remained asymptomatic from anemia and did not require transfusions or treatment. Her disease progressed to MDS with excess blasts 3 years later. Patient was treated with azacitidine. Fifteen months later, her disease further progressed to AML. She passed away 5 months later and four and a half years after initial diagnosis. DNA sequencing analysis of these two cases revealed that the t(2;3)(p23;q26.2) breakpoints were within the regulatory regions of ZFP36L2 and THADA on chromosome 2 and the proximity of MECOM on chromosome 3, creating a novel regulatory configuration for MECOM. Notably, the translocation breakpoints differed by 270 kb on chromosome 2 and 93 kb on chromosome 3, resulting in distinct translocated regulatory elements with varying sizes and proximities to MECOM. These structural differences may influence the level of MECOM upregulation and contribute to variation in disease severity and progression.

[CONCLUSION] Our findings highlighted that, despite cytogenetic similarity, different t(2;3) translocations may exert distinct regulatory effects depending on the precise breakpoint locations. Thus, molecular characterization of MECOM rearrangements is critical for understanding disease pathogenesis and prognosis in myeloid neoplasms and may lead to the development of novel treatment.