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Stem Cells. 2015 Aug;33(8):2628-41. doi: 10.1002/stem.2049. Epub 2015 May 27.

Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.

Author information

1
Department of Cancer Biology.
2
Division of Hematology/Oncology.
3
MRC Molecular Hematology Unit, University of Oxford, Oxford, United Kingdom.
4
Department of Biostatistics, Center for Quantitative Sciences.
5
Division of Medical Genetics, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
6
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
7
Tennessee Valley Healthcare System, Nashville VA, Nashville, Tennessee, USA.

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.

KEYWORDS:

Hematopoiesis; Homeobox; Homeodomain; Lymphopoiesis; Stem cells

PMID:
25968920
PMCID:
PMC4641572
DOI:
10.1002/stem.2049
[Indexed for MEDLINE]
Free PMC Article

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