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

Georgi JA, Stasik S, Eckardt JN, Zukunft S, Hartwig M, Röllig C, Middeke JM, Oelschlägel U, Krug U, Sauer T, Scholl S, Hochhaus A, Brümmendorf TH, Naumann R, Steffen B, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause S, Hänel M, Noppeney R, Kaiser U, Baldus CD, Kaufmann M, Müller-Tidow C, Platzbecker U, Berdel WE, Serve H, Ehninger G, Bornhäuser M, Schetelig J, Kroschinsky F, Thiede C (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 13

Article Number: 88

Journal Issue: 1

DOI: 10.1038/s41408-023-00858-y

Abstract

Tandem-duplication mutations of the UBTF gene (UBTF-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), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 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 UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPA ^bZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-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 UBTF-mutant patients, UBTF-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, p < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p = 0.020]). In summary, UBTF-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.

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Involved external institutions

Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) Klinikum Leverkusen Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) Universitätsklinikum Jena Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE) Klinikum Chemnitz Germany (DE) Universitätsklinikum Essen Germany (DE) St. Bernward Krankenhaus Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Robert-Bosch-Krankenhaus Germany (DE) Universitätsklinikum Leipzig Germany (DE) Universitätsklinikum Münster Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) AvenCell Europe GmbH Germany (DE) St. Marien-Krankenhaus Germany (DE) Universitätsklinikum Würzburg Germany (DE) Rems-Murr-Kliniken Germany (DE) Philipps-Universität Marburg Germany (DE) Klinikum Nürnberg Germany (DE)

How to cite

APA:

Georgi, J.A., Stasik, S., Eckardt, J.N., Zukunft, S., Hartwig, M., Röllig, C.,... Thiede, C. (2023). UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome. Blood Cancer Journal, 13(1). https://doi.org/10.1038/s41408-023-00858-y

MLA:

Georgi, Julia Annabell, et al. "UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome." Blood Cancer Journal 13.1 (2023).

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