title: A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis.
abstract: The hematopoietically expressed homeobox gene, Hhex, is a transcription factor that is important for development of definitive hematopoietic stem cells (HSCs) and B cells, and that causes T-cell leukemia when overexpressed. Here, we have used an Hhex inducible knockout mouse model to study the role of Hhex in adult hematopoiesis. We found that loss of Hhex was tolerated in HSCs and myeloid lineages, but resulted in a progressive loss of B lymphocytes in the circulation. This was accompanied by a complete loss of B-cell progenitors in the bone marrow and of transitional B-cell subsets in the spleen. In addition, transplantation and in vitro culture experiments demonstrated an almost complete failure of Hhex-null HSCs to contribute to lymphoid lineages beyond the common lymphoid precursor stage, including T cells, B cells, NK cells, and dendritic cells. Gene expression analysis of Hhex-deleted progenitors demonstrated deregulated expression of a number of cell cycle regulators. Overexpression of one of these, cyclin D1, could rescue the B-cell developmental potential of Hhex-null lymphoid precursors. Thus, Hhex is a key regulator of early lymphoid development, functioning, at least in part, via regulation of the cell cycle.
authors.affiliation: Division of Cancer and Haematology, and.
authors.forename: Jacob T
authors.identifier: http://orcid.org/0000-0002-6396-2739
authors.initials: JT
authors.lastname: Jackson
authors.affiliation: Division of Cancer and Haematology, and.
authors.forename: Chayanica
authors.initials: C
authors.lastname: Nasa
authors.affiliation: Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Computing and Information Systems, University of Melbourne, Parkville, Australia;
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Department of Medical Biology and Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; and.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Huntington
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Clifford W
authors.initials: CW
authors.lastname: Bogue
authors.affiliation: Division of Cancer and Haematology, and Department of Medical Biology and.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: Division of Cancer and Haematology, and Department of Medical Biology and.
authors.forename: Matthew P
authors.identifier: http://orcid.org/0000-0003-1536-5611
authors.initials: MP
authors.lastname: McCormack
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics* / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006410:Hematopoiesis / Q000235:genetics* / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D038041:Lymphopoiesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000473:pathology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; C513080:Hhex protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D019938:Cyclin D1