title: ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.
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.
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Hartmann
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sayantanee
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Opatz
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Reiter
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Leubolt
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Stefanos A
authors.initials: SA
authors.lastname: Bamopoulos
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Bräundl
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Konstandin
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Biochemistry, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.|Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.|Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, 01307 Dresden, Germany.
authors.forename: Jan Moritz
authors.initials: JM
authors.lastname: Middeke
authors.affiliation: German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.|Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, 01307 Dresden, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Stölzel
authors.affiliation: German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.|Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, 01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.affiliation: German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland 1142, New Zealand.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Hemostasis, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Preiss
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Hemostasis, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Linping
authors.initials: L
authors.lastname: Chen-Wichmann
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Hemostasis, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Sauerland
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pneumology, University of Münster, 48149 Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Department of Medicine A, Hematology, Oncology and Pneumology, University of Münster, 48149 Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, 13353 Berlin, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Wörmann
authors.affiliation: Oncology and Hematology, St. John-of-God Hospital, 93049 Regensburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Braess
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Internal Medicine 3, University Hospital, Ludwig-Maximilians-Universität (LMU) München, 81377 München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 München, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21 / Q000737:chemistry / Q000378:metabolism; D002898:Chromosomes, Human, Pair 8 / Q000737:chemistry / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006019:Glycolysis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D000075142:RUNX1 Translocation Partner 1 Protein / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; C485514:ZBTB7A protein, human