title: The corepressor Tle4 is a novel regulator of murine hematopoiesis and bone development.
abstract: Hematopoiesis is a complex process that relies on various cell types, signaling pathways, transcription factors and a specific niche. The integration of these various components is of critical importance to normal blood development, as deregulation of these may lead to bone marrow failure or malignancy. Tle4, a transcriptional corepressor, acts as a tumor suppressor gene in a subset of acute myeloid leukemia, yet little is known about its function in normal and malignant hematopoiesis or in mammalian development. We report here that Tle4 knockout mice are runted and die at around four weeks with defects in bone development and BM aplasia. By two weeks of age, Tle4 knockout mice exhibit leukocytopenia, B cell lymphopenia, and significant reductions in hematopoietic stem and progenitor cells. Tle4 deficient hematopoietic stem cells are intrinsically defective in B lymphopoiesis and exhaust upon stress, such as serial transplantation. In the absence of Tle4 there is a profound decrease in bone mineralization. In addition, Tle4 knockout stromal cells are defective at maintaining wild-type hematopoietic stem cell function in vitro. In summary, we illustrate a novel and essential role for Tle4 in the extrinsic and intrinsic regulation of hematopoiesis and in bone development.
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Justin C
authors.initials: JC
authors.lastname: Wheat
authors.affiliation: Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Department of Molecular and Translational Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Ding
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Rae'e
authors.initials: R
authors.lastname: Yamin
authors.affiliation: Department of Pediatrics, Divisions of Pediatric Hematology/Oncology and Medical Genetics, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D012097:Repressor Proteins; C434949:Tle4 protein, mouse