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Nat Commun. 2016 Jun 2;7:11733. doi: 10.1038/ncomms11733.

ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

Author information

1
Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
2
Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.
3
German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
4
German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
5
Department of Biochemistry, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
6
Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
7
Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, 01307 Dresden, Germany.
8
Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand.
9
Department of Transfusion Medicine, Cell Therapeutics and Hemostasis, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
10
Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany.
11
Department of Medicine A, Hematology, Oncology and Pneumology, University of Münster, 48149 Münster, Germany.
12
Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, 13353 Berlin, Germany.
13
Oncology and Hematology, St. John-of-God Hospital, 93049 Regensburg, Germany.

Abstract

The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

PMID:
27252013
PMCID:
PMC4895769
DOI:
10.1038/ncomms11733
[Indexed for MEDLINE]
Free PMC Article

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