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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. S tem  C ells   2015;33:2628—2641

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