UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome

Media type: E-Article
Title: UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome
Contributor: Georgi, Julia-Annabell; Stasik, Sebastian; Eckardt, Jan-Niklas; Zukunft, Sven; Hartwig, Marita; Röllig, Christoph; Middeke, Jan Moritz; Oelschlägel, Uta; Krug, Utz; Sauer, Tim; Scholl, Sebastian; Hochhaus, Andreas; Brümmendorf, Tim H.; Naumann, Ralph; Steffen, Björn; Einsele, Hermann; Schaich, Markus; Burchert, Andreas; Neubauer, Andreas; Schäfer-Eckart, Kerstin; Schliemann, Christoph; Krause, Stefan W.; Hänel, Mathias; Noppeney, Richard; [...]
imprint: Springer Science and Business Media LLC, 2023
Published in: Blood Cancer Journal
Language: English
DOI: 10.1038/s41408-023-00858-y
ISSN: 2044-5385
Keywords: Oncology ; Hematology
Origination:
Footnote:
Description: <jats:title>Abstract</jats:title><jats:p>Tandem-duplication mutations of the <jats:italic>UBTF</jats:italic> gene (<jats:italic>UBTF</jats:italic>-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), <jats:italic>FLT3</jats:italic>-internal tandem duplications (<jats:italic>FLT3</jats:italic>-ITD), <jats:italic>WT1</jats:italic>-mutations) and inferior outcome. Due to limited knowledge on <jats:italic>UBTF-</jats:italic>TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. <jats:italic>UBTF</jats:italic>-TDs were overall rare (<jats:italic>n</jats:italic> = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with <jats:italic>UBTF</jats:italic>-TDs had significantly higher rates of +8 (34% vs. 9%), <jats:italic>WT1</jats:italic> (52% vs. 7%) and <jats:italic>FLT3</jats:italic>-ITD (50% vs. 20.8%) co-mutations, whereas <jats:italic>UBTF</jats:italic>-TDs were mutually exclusive with several class-defining lesions such as mutant <jats:italic>NPM1</jats:italic>, in-frame <jats:italic>CEBPA</jats:italic><jats:sup>bZIP</jats:sup> mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (<jats:italic>n</jats:italic> = 5) retained the <jats:italic>UBTF</jats:italic>-TD mutation, <jats:italic>UBTF</jats:italic>-TDs represent early clonal events and are stable over the disease course. In univariate analysis, <jats:italic>UBTF</jats:italic>-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of <jats:italic>UBTF</jats:italic>-mutant patients, <jats:italic>UBTF</jats:italic>-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, <jats:italic>p</jats:italic> < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, <jats:italic>p</jats:italic> = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, <jats:italic>p</jats:italic> = 0.020]). In summary, <jats:italic>UBTF</jats:italic>-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients.</jats:p>
Access State: Open Access

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