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

被引：13

作者：

Georgi, Julia-Annabell ^{[1
]}

Stasik, Sebastian ^{[1
]}

Eckardt, Jan-Niklas ^{[1
]}

Zukunft, Sven ^{[1
]}

Hartwig, Marita ^{[1
]}

Roellig, Christoph ^{[1
]}

Middeke, Jan Moritz ^{[1
]}

Oelschlaegel, Uta ^{[1
]}

Krug, Utz ^{[2
]}

Sauer, Tim ^{[3
]}

Scholl, Sebastian ^{[4
]}

Hochhaus, Andreas H. ^{[4
]}

Bruemmendorf, Tim ^{[5
]}

Naumann, Ralph ^{[6
]}

Steffen, Bjoern ^{[7
]}

Einsele, Hermann ^{[8
]}

Schaich, Markus ^{[9
]}

Burchert, Andreas ^{[10
]}

Neubauer, Andreas ^{[10
]}

Schaefer-Eckart, Kerstin ^{[11
]}

Schliemann, Christoph W. ^{[12
]}

Krause, Stefan ^{[13
]}

Haenel, Mathias ^{[14
]}

Noppeney, Richard ^{[15
]}

Kaiser, Ulrich D. ^{[16
]}

Baldus, Claudia ^{[17
]}

Kaufmann, Martin ^{[18
]}

Mueller-Tidow, Carsten ^{[3
]}

Platzbecker, Uwe E. ^{[19
]}

Berdel, Wolfgang ^{[12
]}

Serve, Hubert ^{[7
]}

Ehninger, Gerhard ^{[20
]}

Bornhaeuser, Martin ^{[1
,21
]}

Schetelig, Johannes ^{[1
,22
]}

Kroschinsky, Frank ^{[1
]}

Thiede, Christian ^{[1
,23
]}

机构：

[1] Univ Klinikum Carl Gustav Carus, Med Klin & Poliklin 1, Dresden, Germany

[2] Klinikum Leverkusen, Med Klin 3, Leverkusen, Germany

[3] Heidelberg Univ, Abt Innere Med 5, Med Klin & Poliklin, Heidelberg, Germany

[4] Univ Klinikum Jena, Klin Innere Med 2, Jena, Germany

[5] Uniklin RWTH Aachen, Med Klin 4, Aachen, Germany

[6] St Marien Krankenhaus Siegen, Med Klin 3, Siegen, Germany

[7] Goethe Univ Frankfurt, Med Klin Hamatol Onkol 2, Frankfurt, Germany

[8] Univ Klinikum Wurzburg, Med Klin & Poliklin 2, Wurzburg, Germany

[9] Rems Murr Klinikum Winnenden, Klin Hamatol Onkol & Palliat Med, Winnenden, Germany

[10] Philipps Univ Marburg, Klin Innere Med Schwerpunkt Hamatol Onkol & Immun, Marburg, Germany

[11] Paracelsus Med Privatuniv, Med Klin 5, Klinikum Nurnberg, Nurnberg, Germany

[12] Univ Klinikum Munster, Med Klin, Munster, Germany

[13] Univ Klinikum Erlangen, Med Klin 5, Erlangen, Germany

[14] Klinikum Chemnitz, Klin Innere Med 3, Chemnitz, Germany

[15] Univ Klinikum Essen, Klin Hamatol, Essen, Germany

[16] St Bernward Krankenhaus, Med Klin 2, Hildesheim, Germany

[17] Univ Klinikum Schleswig Holstein, Klin Innere Med 2, Campus Kiel, Kiel, Germany

[18] Robert Bosch Krankenhaus, Abt Hamatol Onkol & Palliat Med, Stuttgart, Germany

[19] Univ Klinikum Leipzig, Klin & Poliklin Hamatol Zelltherapie & Hamostaseo, Leipzig, Germany

[20] AvenCell Europe GmbH, Dresden, Germany

[21] Natl Ctr Tumor Dis NCT, Dresden, Germany

[22] DKMS Clin Trials Unit, Dresden, Germany

[23] AgenDix GmbH, Dresden, Germany

来源：

BLOOD CANCER JOURNAL | 2023年 / 13卷 / 01期

关键词：

ACUTE MYELOID-LEUKEMIA; POLYMERASE-I TRANSCRIPTION; HEALTH-ORGANIZATION CLASSIFICATION; INTERMEDIATE;

D O I：

10.1038/s41408-023-00858-y

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：8

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