UBTF tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: 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 (UBTF). These alterations, which account for ~4.3% of AMLs in childhood and about 3% in adult AMLs under 60, are sub...

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Published in:Haematologica (Roma) Vol. 109; no. 8; pp. 2459 - 2468
Main Authors: Barajas, Juan M., Umeda, Masayuki, Contreras, Lisett, Khanlari, Mahsa, Westover, Tamara, Walsh, Michael P., Xiong, Emily, Yang, Chenchen, Otero, Brittney, Arribas-Layton, Marc, Abdelhamed, Sherif, Song, Guangchun, Ma, Xiaotu, Thomas 3rd, Melvin E., Ma, Jing, Klco, Jeffery M.
Format: Journal Article
Language:English
Published: Italy Fondazione Ferrata Storti 01.08.2024
Ferrata Storti Foundation
Subjects:
Acute Myeloid Leukemia
ISSN:0390-6078, 1592-8721, 1592-8721
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Summary: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 about 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 celllike 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.
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CY, BO and MA are employed by Mission Bio, Inc. All the other authors have no conflicts of interest to disclose.
Disclosures
ISSN:0390-6078
1592-8721
1592-8721
DOI:10.3324/haematol.2023.284683