title: Exome sequencing identifies highly recurrent somatic GATA2 and CEBPA mutations in acute erythroid leukemia.
abstract: Acute erythroid leukemia (AEL), characterized by a predominant erythroid proliferation, is a subtype of acute myelogenous leukemia. The genetic basis of AEL remains poorly defined. Through whole-exome sequencing, we identified high frequencies of mutations in CEBPA (32.7%), GATA2 (22.4%), NPM1 (15.5%), SETBP1 (12.1%) and U2AF1 (12.1%). Structure prediction analysis revealed that most of the GATA2 mutations were located at the DNA-binding N-terminal zinc-finger near the DNA-binding interface, suggesting that mutations could result in at least partial inactivation of GATA2 protein. On co-transfection of a GATA-responsive reporter construct together with plasmids expressing either GATA2 wild-type or GATA2 ZF1 mutants (P304H, L321P and R330X) in 293T cells, we found a reduced transcriptional activation in cells transfected with GATA2 mutants. To determine whether reduced GATA2 function is involved in leukemogenesis of AEL, we transfected 32D cells with GATA2 mutants and evaluated the impact of GATA2 mutations on erythroid differentiation. Our data revealed an increased expression of erythroid-related antigens Ter-119, β-globin and βh1-globin, as well as increased hemoglobin positivity in 32D cells transfected with GATA2 mutants compared with control cells. Our results suggest that the decline of GATA2 resulting from mutations contributes to the erythroid commitment, differentiation and the development of AEL.
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: N
authors.initials: N
authors.lastname: Ping
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.|Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC.
authors.forename: A
authors.initials: A
authors.lastname: Sun
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, PRC.
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: W
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: L
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.|Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC.
authors.forename: H
authors.initials: H
authors.lastname: Qiu
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.|Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC.
authors.forename: C
authors.initials: C
authors.lastname: Ruan
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.|Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC.
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC.|Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC.
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D041905:Erythroid Cells; D059472:Exome / Q000235:genetics*; D050989:GATA2 Transcription Factor / Q000235:genetics*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics*; D009154:Mutation; D000090243:Nucleophosmin; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D050989:GATA2 Transcription Factor; C000716967:NPM1 protein, human; D000090243:Nucleophosmin