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.

C.Y., B.O., and M.A. are employed by Mission Bio, Inc. No other authors have conflicts to declare.

The work was funded by the American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital and funds from the US NIH, including F32 HL154636 (JMB), U54 CA243124 and R01 CA276079 (JMK). The content, however, does not necessarily represent the official views of the NIH and is solely the responsibility of the authors. The studies were also funded by the Jane Coffin Childs Fund (JMB). JMK holds a Career Award for Medical Scientists from the Burroughs Welcome Fund. Support was also provided by Shared Resources provided through the St. Jude Comprehensive Cancer Center (P30-CA21765), Flow Cytometry and Cell Sorting, Comparative Pathology Core, and Genome Sequencing (Hartwell Center).

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Samples from patients with MDS or AML from St. Jude Childrens Research Hospital tissue resource core facility were obtained with written informed consent using a protocol approved by the St. Jude Childrens Research Hospital institutional review board (IRB). Studies were conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects

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The expression data newly generated in this study (RNA-Seq: n=3) and scDNA + protein sequencing (n=3) have been deposited in the European Genome-Phenome Archive (EGA) which is hosted by the European Bioinformatics Institute (EBI), under accession EGAS00001005760. The remaining RNA-Seq data are available via EGA, St. Jude Cloud or TARGET as defined in Supplemental Table 6. Information about TARGET can be found at http://ocg.cancer.gov/programs/target. Other data generated in this study are available in the Supplemental tables or upon request to the corresponding author.