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

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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 ( UBTF ). 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 UBTF -TD myeloid neoplasms in childhood, including 89 unique pediatric AML and 6 myelodysplastic syndrome (MDS) cases harboring a tandem duplication in exon 13 of UBTF . We demonstrate that UBTF- 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 UBTF -TD is an early and clonal event associated with a distinct transcriptional profile, whereas the acquisition of FLT3 or WT1 mutations is associated with more stem cell-like programs. Lastly, we report rare duplications within exon 9 of UBTF that phenocopy exon 13 duplications, expanding the spectrum of UBTF alterations in pediatric myeloid tumors. Collectively, we comprehensively characterize pediatric AML and MDS with UBTF- TD and highlight key clinical and pathologic features that distinguish this new entity from other molecular subtypes of AML. Key Points Largest cohort of pediatric UBTF- TD in myeloid neoplasms reported to date. Use of single-cell DNA+protein sequencing technology in 3 UBTF- TD samples reveals a clonal evaluation pattern characterized by sequential acquisition of WT1 and FLT3 mutations and a more stem cell-like protein expression pattern. Pediatric MDS and AML patients with UBTF- TD alterations dysplastic features with an increase erythroid precursors. Tandem duplications in exon 9 of UBTF represent a rare but functionally equivalent subgroup of UBTF- TD myeloid neoplasms. Impact Statement UBTF tandem duplications (TD) are subtype-defining genomic alterations in adult and pediatric myeloid neoplasms. Here, we provide a comprehensive characterization of the largest cohort of pediatric UBTF -TD cases to date, including the recognition of additional UBTF alterations that mimic the exon 13 duplications in pediatric AML.