title: Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.
abstract: Hhex encodes a homeodomain transcription factor that is widely expressed in hematopoietic stem and progenitor cell populations. Its enforced expression induces T-cell leukemia and we have implicated it as an important oncogene in early T-cell precursor leukemias where it is immediately downstream of an LMO2-associated protein complex. Conventional Hhex knockouts cause embryonic lethality precluding analysis of adult hematopoiesis. Thus, we induced highly efficient conditional knockout (cKO) using vav-Cre transgenic mice. Hhex cKO mice were viable and born at normal litter sizes. At steady state, we observed a defect in B-cell development that we localized to the earliest B-cell precursor, the pro-B-cell stage. Most remarkably, bone marrow transplantation using Hhex cKO donor cells revealed a more profound defect in all hematopoietic lineages. In contrast, sublethal irradiation resulted in normal myeloid cell repopulation of the bone marrow but markedly impaired repopulation of T- and B-cell compartments. We noted that Hhex cKO stem and progenitor cell populations were skewed in their distribution and showed enhanced proliferation compared to WT cells. Our results implicate Hhex in the maintenance of LT-HSCs and in lineage allocation from multipotent progenitors especially in stress hematopoiesis.
authors.affiliation: Department of Cancer Biology.|Division of Hematology/Oncology.
authors.forename: Charnise
authors.initials: C
authors.lastname: Goodings
authors.affiliation: Division of Hematology/Oncology.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith
authors.affiliation: Division of Hematology/Oncology.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mathias
authors.affiliation: MRC Molecular Hematology Unit, University of Oxford, Oxford, United Kingdom.
authors.forename: Natalina
authors.initials: N
authors.lastname: Elliott
authors.affiliation: Division of Hematology/Oncology.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cleveland
authors.affiliation: Division of Hematology/Oncology.
authors.forename: Rati M
authors.initials: RM
authors.lastname: Tripathi
authors.affiliation: Division of Hematology/Oncology.
authors.forename: Justin H
authors.initials: JH
authors.lastname: Layer
authors.affiliation: Department of Biostatistics, Center for Quantitative Sciences.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Center for Quantitative Sciences.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Biostatistics, Center for Quantitative Sciences.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Hamid
authors.affiliation: Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Cancer Biology.|Division of Hematology/Oncology.|Tennessee Valley Healthcare System, Nashville VA, Nashville, Tennessee, USA.
authors.forename: Utpal P
authors.initials: UP
authors.lastname: Davé
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors
keywords: Hematopoiesis; Homeobox; Homeodomain; Lymphopoiesis; Stem cells