Tandem Duplications in Pediatric MDS and AML: Implications for Clinical Screening and Diagnosis.

Recent genomic studies in adult and pediatric acute myeloid leukemia (AML) demonstrated recurrent in-frame tandem duplications (TD) in exon 13 of upstream binding transcription factor (). These alterations, which account for ~4.3% of AMLs in childhood and up to 3% in adult AMLs under 60, are subtype-defining and associated with poor outcomes. Here, we provide a comprehensive investigation into the clinicopathological features of -TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of . We demonstrate that -TD myeloid tumors are associated with dysplastic features, low bone marrow blast infiltration, and low white blood cell count. Furthermore, using bulk and single-cell analyses, we confirm that -TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of or mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of that phenocopy exon 13 duplications, expanding the spectrum of alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with -TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML.