Abstract
Double minutes (dmins), a form of extrachromosomal DNA (ecDNA), represent a rare cytogenomic event in myeloid neoplasms and are most commonly associated with amplification of oncogenes such as MYC or KMT2A. Dmins derived from the 11q24 region that exclude KMT2A are exceedingly uncommon, and their pathogenic significance remains poorly understood. We report a 74-year-old female initially diagnosed with myelodysplastic syndrome (MDS) with isolated del(5) (q13q33) and mutations in TP53 and SF3B1. After eight years and treatment with lenalidomide with excellent clinical response, she developed progressive cytopenias and transformation to acute myeloid leukemia, myelodysplasia-related (AML-MR). Cytogenomic analysis at the time of leukemic transformation revealed del(5) (q13q33) in all 20 metaphase cells analyzed and loss of the EGR1 (5q31.2) gene in 94% of interphase nuclei by fluorescence in situ hybridization (FISH). Notably, 18 of 20 metaphase cells also harbored dmins, ranging from 2 to 22 copies per cell. Array-based comparative genomic hybridization and single nucleotide polymorphism array (array-CGH + SNP) identified a 5.57 Mb amplification of chromosome 11q24.2-q25 encompassing at least 40 genes, including FLI1 and ETS1 but excluding KMT2A. Metaphase FISH confirmed localization of the amplified 11q24 segment within the dmins, and immunohistochemistry demonstrated nuclear FLI1 expression in myeloblasts. The patient was treated with combination azacitidine and venetoclax and an investigational immunotherapy within a clinical trial. This case represents the third reported instance of dmins derived from the 11q24 region involving FLI1 and ETS1 and the first identified in the context of AML evolved from del(5q) MDS. Dmins in myeloid neoplasms have been linked to genomic instability, clonal evolution, and therapeutic resistance. Amplification and expression of FLI1 in blasts, a hematopoietic transcription factor implicated in leukemogenesis and poor prognosis in AML, suggest a potential pathogenic role for 11q24-derived dmins in disease progression. Our findings expand the spectrum of dmin-associated oncogenic amplifications in myeloid neoplasms and highlight FLI1 and ETS1 as recurrent targets of 11q24-derived ecDNA amplification. Recognition of such rare events underscores the importance of integrative cytogenomic profiling for uncovering novel mechanisms of leukemic transformation and potential therapeutic targets.