A crucial role for the homeodomain transcription factor Hhex in lymphopoiesis

• Published in: Blood 2015-01, Vol.125 (5), p.803-814
• Main Authors: Jackson, Jacob T., Nasa, Chayanica, Shi, Wei, Huntington, Nicholas D., Bogue, Clifford W., Alexander, Warren S., McCormack, Matthew P.
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Cell Cycle Proteins - genetics; Cell Cycle Proteins - immunology; Cell Differentiation; Cell Proliferation; Cyclin D1 - genetics; Cyclin D1 - immunology; Dendritic Cells - immunology; Dendritic Cells - pathology; Gene Deletion; Gene Expression Regulation; Genetic Complementation Test; Hematopoiesis - genetics; Hematopoiesis - immunology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - pathology; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Killer Cells, Natural - immunology; Killer Cells, Natural - pathology; Lymphocyte Count; Lymphocyte Depletion; Lymphopoiesis - genetics; Lymphopoiesis - immunology; Mice; Mice, Knockout; Precursor Cells, B-Lymphoid - immunology; Precursor Cells, B-Lymphoid - pathology; Spleen - immunology; Spleen - pathology; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - immunology; Transcription, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-06-579813

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. •Hhex regulates development of diverse lymphoid lineages.•Hhex regulates cycling of lymphoid precursors.