biostudies-literature00470Goodings CBLRD VAthe Microenvironmental Influences in CancerDepartment of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and DevelopmentNIDDK NIH HHSInitiative for Maximizing Student DevelopmentVanderbilt Digestive Disease Research CenterNHLBI NIH HHSNHGRI NIH HHSNCI NIH HHSNIGMS NIH HHSVanderbilt Ingram Cancer Center2628-41https://www.ebi.ac.uk/biostudies/studies/S-EPMC4641572biostudies-literatureUnknown33(8)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.Stem cells (Dayton, Ohio)Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.PMC4641572R01 HL102020(P30 CA68485)P30 DK058404P30CA68485U01 HG007674T32 CA009592P30 CA68485I01 BX001799K08 HL089903(BX001799-01A1)F31HL117624(R25GM062459)P30 CA068485F31 HL117624R25GM062459(T32CA009592)(DK058404)DK058404R25 GM062459Guo YElliott NDu YSmith ETripathi RMShyr YDave UPGoodings CHamid RChen XCleveland SMLayer JHMathias E47falseHhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.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.2015-01-01T00:00:00Z2015 Aug2024-11-06T03:52:42.673Z2019-03-27T02:01:45ZS-EPMC46415722596892010.1002/stem.2049