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

Luise Hartmann; Sayantanee Dutta; Sabrina Opatz; Sebastian Vosberg; Katrin Reiter; Georg Leubolt; Klaus H Metzeler; Tobias Herold; Stefanos A Bamopoulos; Kathrin Bräundl; Evelyn Zellmeier; Bianka Ksienzyk; Nikola P Konstandin; Stephanie Schneider; Karl-Peter Hopfner; Alexander Graf; Stefan Krebs; Helmut Blum; Jan Moritz Middeke; Friedrich Stölzel; Christian Thiede; Stephan Wolf; Stefan K Bohlander; Caroline Preiss; Linping Chen-Wichmann; Christian Wichmann; Maria Cristina Sauerland; Thomas Büchner; Wolfgang E Berdel; Bernhard J Wörmann; Jan Braess; Wolfgang Hiddemann; Karsten Spiekermann; Philipp A Greif

doi:10.1038/ncomms11733

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

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

Authors

Luise Hartmann^{1

2

3

4}, Sayantanee Dutta^{1

2

3

4}, Sabrina Opatz^{1

2

3

4}, Sebastian Vosberg^{1

2

3

4}, Katrin Reiter^{1

2

3

4}, Georg Leubolt^{1

2

3

4}, Klaus H Metzeler^{1

2

3

4}, Tobias Herold^{1

2

3

4}, Stefanos A Bamopoulos¹, Kathrin Bräundl^{1

2

3

4}, Evelyn Zellmeier¹, Bianka Ksienzyk¹, Nikola P Konstandin¹, Stephanie Schneider¹, Karl-Peter Hopfner⁵, Alexander Graf⁶, Stefan Krebs⁶, Helmut Blum^{3

4

6}, Jan Moritz Middeke^{3

4

7}, Friedrich Stölzel^{3

4

7}, Christian Thiede^{3

4

7}, Stephan Wolf⁴, Stefan K Bohlander⁸, Caroline Preiss⁹, Linping Chen-Wichmann⁹, Christian Wichmann⁹, Maria Cristina Sauerland¹⁰, Thomas Büchner¹¹, Wolfgang E Berdel¹¹, Bernhard J Wörmann¹², Jan Braess¹³, Wolfgang Hiddemann^{1

2

3

4}, Karsten Spiekermann^{1

2

3

4}, Philipp A Greif^{1

2

3

4}

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Cell Line, Tumor
Chromosomes, Human, Pair 21 / chemistry
Chromosomes, Human, Pair 21 / metabolism
Chromosomes, Human, Pair 8 / chemistry
Chromosomes, Human, Pair 8 / metabolism
Core Binding Factor Alpha 2 Subunit / genetics*
Core Binding Factor Alpha 2 Subunit / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Profiling
Gene Expression Regulation, Leukemic*
Glycolysis / genetics
HEK293 Cells
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / mortality
Leukemia, Myeloid, Acute / pathology
Mutation*
Oncogene Proteins, Fusion / genetics*
Oncogene Proteins, Fusion / metabolism
Protein Domains
RUNX1 Translocation Partner 1 Protein / genetics*
RUNX1 Translocation Partner 1 Protein / metabolism
Signal Transduction
Survival Analysis
Transcription Factors / genetics*
Transcription Factors / metabolism
Translocation, Genetic*

Substances

AML1-ETO fusion protein, human
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins
Oncogene Proteins, Fusion
RUNX1 Translocation Partner 1 Protein
RUNX1 protein, human
RUNX1T1 protein, human
Transcription Factors
ZBTB7A protein, human