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Hhex is Required at Multiple Stages of Adult Hematopoietic Stem and Progenitor Cell Differentiation.
Goodings C, Smith E, Mathias E, Elliott N, Cleveland SM, Tripathi RM, Layer JH, Chen X, Guo Y, Shyr Y, Hamid R, Du Y, Davé UP
(2015) Stem Cells 33: 2628-41
MeSH Terms: Animals, Cell Differentiation, Hematopoiesis, Hematopoietic Stem Cells, Homeodomain Proteins, Mice, Mice, Knockout, Precursor Cells, B-Lymphoid, Precursor Cells, T-Lymphoid, Transcription Factors
Show Abstract · Added February 22, 2016
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 AlphaMed Press.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia.
Cleveland SM, Smith S, Tripathi R, Mathias EM, Goodings C, Elliott N, Peng D, El-Rifai W, Yi D, Chen X, Li L, Mullighan C, Downing JR, Love P, Davé UP
(2013) Stem Cells 31: 882-94
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Differentiation, Cell Lineage, Gene Expression, Hematopoietic Stem Cells, LIM Domain Proteins, Leukemia, T-Cell, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, T-Lymphoid
Show Abstract · Added September 3, 2013
LIM domain only 2 (Lmo2) is frequently deregulated in sporadic and gene therapy-induced acute T-cell lymphoblastic leukemia (T-ALL) where its overexpression is an important initiating mutational event. In transgenic and retroviral mouse models, Lmo2 expression can be enforced in multiple hematopoietic lineages but leukemia only arises from T cells. These data suggest that Lmo2 confers clonal growth advantage in T-cell progenitors. We analyzed proliferation, differentiation, and cell death in CD2-Lmo2 transgenic thymic progenitor cells to understand the cellular effects of enforced Lmo2 expression. Most impressively, Lmo2 transgenic T-cell progenitor cells were blocked in differentiation, quiescent, and immortalized in vitro on OP9-DL1 stromal cells. These cellular effects were concordant with a transcriptional signature in Lmo2 transgenic T-cell progenitor cells that is also present in hematopoietic stem cells (HSCs) and early T-cell precursor ALL. These results are significant in light of the crucial role of Lmo2 in the maintenance of the HSC. The cellular effects and transcriptional effects have implications for LMO2-dependent leukemogenesis and the treatment of LMO2-induced T-ALL.
Copyright © 2013 AlphaMed Press.
0 Communities
4 Members
0 Resources
12 MeSH Terms
Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.
Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, Cheroutre H
(2011) Nat Immunol 12: 1086-95
MeSH Terms: Animals, Antigens, CD8 Antigens, Cell Differentiation, Clonal Selection, Antigen-Mediated, Dendritic Cells, Immunity, Mucosal, Immunologic Memory, Listeriosis, Lymphocyte Activation, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, T-Lymphoid, T-Lymphocytes, Transgenes
Show Abstract · Added March 20, 2014
The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αβ(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αβ(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αβ(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αβ(+) memory T cells that form the first line of defense at the largest entry port for pathogens.
0 Communities
2 Members
0 Resources
17 MeSH Terms
Functional interactions between Lmo2, the Arf tumor suppressor, and Notch1 in murine T-cell malignancies.
Treanor LM, Volanakis EJ, Zhou S, Lu T, Sherr CJ, Sorrentino BP
(2011) Blood 117: 5453-62
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Transformation, Neoplastic, Cocarcinogenesis, Cyclin-Dependent Kinase Inhibitor p16, DNA-Binding Proteins, Disease Progression, Female, Gene Expression, LIM Domain Proteins, Loss of Heterozygosity, Male, Metalloproteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Neoplastic Stem Cells, Precursor Cells, T-Lymphoid, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic, Receptor, Notch1, Signal Transduction
Show Abstract · Added May 27, 2014
LMO2 is a target of chromosomal translocations in T-cell tumors and was activated by retroviral vector insertions in T-cell tumors from X-SCID patients in gene therapy trials. To better understand the cooperating genetic events in LMO2-associated T-cell acute lymphoblastic leukemia (T-ALL), we investigated the roles of Arf tumor suppressor loss and Notch activation in murine models of transplantation. Lmo2 overexpression enhanced the expansion of primitive DN2 thymocytes, eventually facilitating the stochastic induction of clonal CD4(+)/CD8(+) malignancies. Inactivation of the Arf tumor suppressor further increased the self-renewal capacity of the primitive, preleukemic thymocyte pool and accelerated the development of aggressive, Lmo2-induced T-cell lympholeukemias. Notch mutations were frequently detected in these Lmo2-induced tumors. The Arf promoter was not directly engaged by Lmo2 or mutant Notch, and use of a mouse model in which activation of a mutant Notch allele depends on previous engagement of the Arf promoter revealed that Notch activation could occur as a subsequent event in T-cell tumorigenesis. Therefore, Lmo2 cooperates with Arf loss to enhance self-renewal in primitive thymocytes. Notch mutation and Arf inactivation appear to independently cooperate in no requisite order with Lmo2 overexpression in inducing T-ALL, and all 3 events remained insufficient to guarantee immediate tumor development.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Proteasome inhibition drastically but reversibly impairs murine lymphocyte development.
Maseda D, Meister S, Neubert K, Herrmann M, Voll RE
(2008) Cell Death Differ 15: 600-12
MeSH Terms: Animals, Apoptosis, B-Lymphocyte Subsets, Bone Marrow Cells, Boronic Acids, Bortezomib, Cells, Cultured, Female, Lymphocyte Count, Lymphoid Tissue, Mice, Mice, Inbred BALB C, NF-kappa B, Precursor Cells, B-Lymphoid, Precursor Cells, T-Lymphoid, Protease Inhibitors, Proteasome Inhibitors, Protein Folding, Pyrazines, T-Lymphocyte Subsets, Thymus Gland
Show Abstract · Added September 17, 2013
The proteasome inhibitor bortezomib, which induces cell death in various cancer cell lines including lymphatic neoplasias, has recently been approved for the treatment of relapsed multiple myeloma. Important mechanisms of proteasome inhibitor-mediated tumor cell death are the inhibition of NF-kappaB activation and induction of the terminal unfolded protein response (UPR). However, little is known about effects of bortezomib on developing and mature lymphocytes. Therefore, Balb/C mice were injected with bortezomib and lymphocyte subsets were analyzed. This treatment resulted in dramatically decreased numbers of T and B lymphocyte precursors, while mature lymphocytes were only partially affected. Thymocytes were almost depleted 3 days after a single bortezomib injection, pro-B and pre-B cells already after 2 days. Thymocytes and B cell precursors recovered within 2 weeks. The decreased numbers of developing lymphocytes were due to apoptotic cell death accompanied by strongly increased caspase 3/7 activity. Within 8 h after bortezomib injection, there was a strong induction of heat shock protein 70 and C/EBP homologous protein in bone marrow B cells, indicating endoplasmic reticulum stress and activation of the terminal UPR, respectively. Hence, induction of apoptosis by proteasome inhibition can dramatically affect lymphocyte development, a fact which has important implications for the clinical use of bortezomib, especially in situations with ongoing lymphopoiesis.
0 Communities
1 Members
0 Resources
21 MeSH Terms