title: Gata3 restrains B cell proliferation and cooperates with p18INK4c to repress B cell lymphomagenesis.
abstract: GATA3, a lineage specifier, controls lymphoid cell differentiation and its function in T cell commitment and development has been extensively studied. GATA3 promotes T cell specification by repressing B cell potential in pro T cells and decreased GATA3 expression is essential for early B cell commitment. Inherited genetic variation in GATA3 has been associated with lymphoma susceptibility. However, it remains elusive how the loss of function of GATA3 promotes B cell development and induces B cell lymphomas. In this study, we found that haploid loss of Gata3 by heterozygous germline deletion increased B cell populations in the bone marrow (BM) and spleen, and decreased CD4 T cell populations in the thymus, confirming that Gata3 promotes T and suppresses B cell development. We discovered that haploid loss of Gata3 reduced thymocyte proliferation with induction of p18Ink4c (p18), an inhibitor of CDK4 and CDK6, but enhanced B cell proliferation in the BM and spleen independent of p18. Loss of p18 partially restored Gata3 deficient thymocyte proliferation, but further stimulated Gata3 deficient B cell proliferation in the BM and spleen. Furthermore, we discovered that haploid loss of Gata3 in p18 deficient mice led to the development of B cell lymphomas that were capable of rapidly regenerating tumors when transplanted into immunocompromised mice. These results indicate that Gata3 deficiency promotes B cell differentiation and proliferation, and cooperates with p18 loss to induce B cell lymphomas. This study, for the first time, reveals that Gata3 is a tumor suppressor specifically in B cell lymphomagenesis.
authors: Department of Hematology, Peking University First Hospital, Beijing, 100034, China.|Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Shiqin
authors: S
authors: Liu
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Ho Lam
authors: HL
authors: Chan
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Feng
authors: F
authors: Bai
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.|Xinjiang Uigur Autonomous Region People's Hospital, Xinjiang, 830001, China.
authors: Jinshan
authors: J
authors: Ma
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.|The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Alexandria
authors: A
authors: Scott
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: David J
authors: DJ
authors: Robbins
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Anthony J
authors: AJ
authors: Capobianco
authors: Department of Hematology, Peking University First Hospital, Beijing, 100034, China.
authors: Ping
authors: P
authors: Zhu
authors: Molecular Oncology Program, Division of Surgical Oncology, Department of Surgery, Miller School of Medicine, University of Miami, FL 33136, Miami.|The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, FL 33136, Miami.|Sylvester Cancer Center, Miller School of Medicine, University of Miami, FL 33136, Miami.
authors: Xin-Hai
authors: XH
authors: Pei
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism*; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism*; D017353:Gene Deletion; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006579:Heterozygote; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D019656:Loss of Heterozygosity; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000378:metabolism*; D051379:Mice; D013154:Spleen / Q000166:cytology; D060168:Thymocytes / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
chemical_list: C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007143:Immunoglobulin Heavy Chains; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6
keywords: B cell; Gata3; lymphoma; p18INK4c