Publications

@article{VanVlierberghe2010,

title = {PHF6 mutations in T-cell acute lymphoblastic leukemia.},

author = {Pieter Van Vlierberghe and Teresa Palomero and Hossein Khiabanian and Joni Van der Meulen and Mireia Castillo and Nadine Van Roy and Barbara De Moerloose and Jan Philippé and Sara González-García and María L Toribio and Tom Taghon and Linda Zuurbier and Barbara Cauwelier and Christine J Harrison and Claire Schwab and Markus Pisecker and Sabine Strehl and Anton W Langerak and Jozef Gecz and Edwin Sonneveld and Rob Pieters and Elisabeth Paietta and Jacob M Rowe and Peter H Wiernik and Yves Benoit and Jean Soulier and Bruce Poppe and Xiaopan Yao and Carlos Cordon-Cardo and Jules Meijerink and Raul Rabadan and Frank Speleman and Adolfo Ferrando},

doi = {10.1038/ng.542},

issn = {1546-1718},

year  = {2010},

date = {2010-04-01},

journal = {Nature genetics},

volume = {42},

pages = {338--342},

abstract = {Tumor suppressor genes on the X chromosome may skew the gender distribution of specific types of cancer. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with an increased incidence in males. In this study, we report the identification of inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL samples. Notably, PHF6 mutations are almost exclusively found in T-ALL samples from male subjects. Mutational loss of PHF6 is importantly associated with leukemias driven by aberrant expression of the homeobox transcription factor oncogenes TLX1 and TLX3. Overall, these results identify PHF6 as a new X-linked tumor suppressor in T-ALL and point to a strong genetic interaction between PHF6 loss and aberrant expression of TLX transcription factors in the pathogenesis of this disease.},

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}

@article{VanCoppernolle2009,

title = {Functionally mature CD4 and CD8 TCRalphabeta cells are generated in OP9-DL1 cultures from human CD34+ hematopoietic cells.},

author = {Stefanie Van Coppernolle and Greet Verstichel and Frank Timmermans and Imke Velghe and David Vermijlen and Magda De Smedt and Georges Leclercq and Jean Plum and Tom Taghon and Bart Vandekerckhove and Tessa Kerre},

doi = {10.4049/jimmunol.0900714},

issn = {1550-6606},

year  = {2009},

date = {2009-10-01},

journal = {Journal of immunology (Baltimore, Md. : 1950)},

volume = {183},

pages = {4859--4870},

abstract = {Human CD34(+) hematopoietic precursor cells cultured on delta-like ligand 1 expressing OP9 (OP9-DL1) stromal cells differentiate to T lineage cells. The nature of the T cells generated in these cultures has not been studied in detail. Since these cultures do not contain thymic epithelial cells which are the main cell type mediating positive selection in vivo, generation of conventional helper CD4(+) and cytotoxic CD8(+) TCRalphabeta cells is not expected. Phenotypically mature CD27(+)CD1(-) TCRgammadelta as well as TCRalphabeta cells were generated in OP9-DL1 cultures. CD8 and few mature CD4 single-positive TCRalphabeta cells were observed. Mature CD8 single-positive cells consisted of two subpopulations: one expressing mainly CD8alphabeta and one expressing CD8alphaalpha dimers. TCRalphabeta CD8alphaalpha and TCRgammadelta cells both expressed the IL2Rbeta receptor constitutively and proliferated on IL-15, a characteristic of unconventional T cells. CD8alphabeta(+) and CD4(+) TCRalphabeta cells were unresponsive to IL-15, but could be expanded upon TCR stimulation as mature CD8alphabeta(+) and CD4(+) T cells. These T cells had the characteristics of conventional T cells: CD4(+) cells expressed ThPOK, CD40L, and high levels of IL-2 and IL-4; CD8(+) cells expressed Eomes, Runx3, and high levels of granzyme, perforin, and IFN-gamma. Induction of murine or human MHC class I expression on OP9-DL1 cells had no influence on the differentiation of mature CD8(+) cells. Similarly, the presence of dendritic cells was not required for the generation of mature CD4(+) or CD8(+) T cells. These data suggest that positive selection of these cells is induced by interaction between T precursor cells.},

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@article{Timmermans2009,

title = {Generation of T cells from human embryonic stem cell-derived hematopoietic zones.},

author = {Frank Timmermans and Imke Velghe and Lieve Vanwalleghem and Magda De Smedt and Stefanie Van Coppernolle and Tom Taghon and Harry D Moore and Georges Leclercq and Anton W Langerak and Tessa Kerre and Jean Plum and Bart Vandekerckhove},

doi = {10.4049/jimmunol.0803670},

issn = {1550-6606},

year  = {2009},

date = {2009-06-01},

journal = {Journal of immunology (Baltimore, Md. : 1950)},

volume = {182},

pages = {6879--6888},

abstract = {Human embryonic stem cells (hESC) are pluripotent stem cells. A major challenge in the field of hESC is the establishment of specific differentiation protocols that drives hESC down a particular lineage fate. So far, attempts to generate T cells from hESC in vitro were unsuccessful. In this study, we show that T cells can be generated in vitro from hESC-derived hematopoietic precursor cells present in hematopoietic zones (HZs). These zones are morphologically similar to blood islands during embryonic development, and are formed when hESC are cultured on OP9 stromal cells. Upon subsequent transfer of these HZs on OP9 cells expressing high levels of Delta-like 1 and in the presence of growth factors, cells expand and differentiate to T cells. Furthermore, we show that T cells derive exclusively from a CD34(high)CD43(low) population, further substantiating the notion that hESC-derived CD34(high)CD43(low) cells are formed in HZs and are the only population containing multipotent hematopoietic precursor cells. Differentiation to T cells sequentially passes through the physiological intermediates: CD34(+)CD7(+) T/NK committed, CD7(+)CD4(+)CD8(-) immature single positive, CD4(+)CD8(+) double positive, and finally CD3(+)CD1(-)CD27(+) mature T cell stages. TCRalphabeta(+) and TCRgammadelta(+) T cells are generated. Mature T cells are polyclonal, proliferate, and secrete cytokines in response to mitogens. This protocol for the de novo generation of T cells from hESC could be clinically and scientifically relevant.},

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@article{Taghon2009,

title = {Notch signaling is required for proliferation but not for differentiation at a well-defined beta-selection checkpoint during human T-cell development.},

author = {Tom Taghon and Inge Van de Walle and Greet De Smet and Magda De Smedt and Georges Leclercq and Bart Vandekerckhove and Jean Plum},

doi = {10.1182/blood-2008-07-168906},

issn = {1528-0020},

year  = {2009},

date = {2009-04-01},

journal = {Blood},

volume = {113},

pages = {3254--3263},

abstract = {Notch signaling is absolutely required for beta-selection during mouse T-cell development, both for differentiation and proliferation. In this report, we investigated whether Notch has an equally important role during human T-cell development. We show that human CD34(+) thymocytes can differentiate into CD4(+)CD8beta(+) double positive (DP) thymocytes in the absence of Notch signaling. While these DP cells phenotypically resemble human beta-selected cells, they lack a T-cell receptor (TCR)-beta chain. Therefore, we characterized the beta-selection checkpoint in human T-cell development, using CD28 as a differential marker at the immature single positive CD4(+)CD3(-)CD8alpha(-) stage. Through intracellular TCR-beta staining and gene expression analysis, we show that CD4(+)CD3(-)CD8alpha(-)CD28(+) thymocytes have passed the beta-selection checkpoint, in contrast to CD4(+)CD3(-)CD8alpha(-)CD28(-) cells. These CD4(+)CD3(-)CD8alpha(-)CD28(+) thymocytes can efficiently differentiate into CD3(+)TCRalphabeta(+) human T cells in the absence of Notch signaling. Importantly, preselection CD4(+)CD3(-)CD8alpha(-)CD28(-) thymocytes can also differentiate into CD3(+)TCRalphabeta(+) human T cells without Notch activation when provided with a rearranged TCR-beta chain. Proliferation of human thymocytes, however, is clearly Notch-dependent. Thus, we have characterized the beta-selection checkpoint during human T-cell development and show that human thymocytes require Notch signaling for proliferation but not for differentiation at this stage of development.},

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@article{VandeWalle2009,

title = {An early decrease in Notch activation is required for human TCR-alphabeta lineage differentiation at the expense of TCR-gammadelta T cells.},

author = {Inge Van de Walle and Greet De Smet and Magda De Smedt and Bart Vandekerckhove and Georges Leclercq and Jean Plum and Tom Taghon},

doi = {10.1182/blood-2008-06-164871},

issn = {1528-0020},

year  = {2009},

date = {2009-03-01},

journal = {Blood},

volume = {113},

pages = {2988--2998},

abstract = {Although well characterized in the mouse, the role of Notch signaling in the human T-cell receptor alphabeta (TCR-alphabeta) versus TCR-gammadelta lineage decision is still unclear. Although it is clear in the mouse that TCR-gammadelta development is less Notch dependent compared with TCR-alphabeta differentiation, retroviral overexpression studies in human have suggested an opposing role for Notch during human T-cell development. Using the OP9-coculture system, we demonstrate that changes in Notch activation are differentially required during human T-cell development. High Notch activation promotes the generation of T-lineage precursors and gammadelta T cells but inhibits differentiation toward the alphabeta lineage. Reducing the amount of Notch activation rescues alphabeta-lineage differentiation, also at the single-cell level. Gene expression analysis suggests that this is mediated by differential sensitivities of Notch target genes in response to changes in Notch activation. High Notch activity increases DTX1, NRARP, and RUNX3 expression, genes that are down-regulated during alphabeta-lineage differentiation. Furthermore, increased interleukin-7 levels cannot compensate for the Notch dependent TCR-gammadelta development. Our results reveal stage-dependent molecular changes in Notch signaling that are critical for normal human T-cell development and reveal fundamental molecular differences between mouse and human.},

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@article{Taghon2008,

title = {Molecular mechanisms that control mouse and human TCR-alphabeta and TCR-gammadelta T cell development.},

author = {Tom Taghon and Ellen V Rothenberg},

doi = {10.1007/s00281-008-0134-3},

issn = {1863-2297},

year  = {2008},

date = {2008-12-01},

journal = {Seminars in immunopathology},

volume = {30},

pages = {383--398},

abstract = {Following specification of hematopoietic precursor cells into the T cell lineage, several developmental options remain available to the immature thymocytes. The paradigm is that the outcome of the T cell receptor rearrangements and the corresponding T cell receptor signaling events will be predominant to determine the first of these choices: the alphabeta versus gammadelta T cell pathways. Here, we review the thymus-derived environmental signals, the transcriptional mediators, and other molecular mechanisms that are also involved in this decision in both the mouse and human. We discuss the differences in cellular events between the alphabeta and gammadelta developmental pathways and try to correlate these with a corresponding complexity of the molecular mechanisms that support them.},

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@article{VanDenBroeck2008,

title = {Ly49E-dependent inhibition of natural killer cells by urokinase plasminogen activator.},

author = {Tina Van Den Broeck and Frederik Stevenaert and Sylvie Taveirne and Veronique Debacker and Christel Vangestel and Bart Vandekerckhove and Tom Taghon and Patrick Matthys and Jean Plum and Werner Held and Mieke Dewerchin and Wayne M Yokoyama and Georges Leclercq},

doi = {10.1182/blood-2008-06-164350},

issn = {1528-0020},

year  = {2008},

date = {2008-12-01},

journal = {Blood},

volume = {112},

pages = {5046--5051},

abstract = {The Ly49 natural killer (NK)-cell receptor family comprises both activating and inhibitory members, which recognize major histocompatibility complex (MHC) class I or MHC class I-related molecules and are involved in target recognition. As previously shown, the Ly49E receptor fails to bind to a variety of soluble or cell-bound MHC class I molecules, indicating that its ligand is not an MHC class I molecule. Using BWZ.36 reporter cells, we demonstrate triggering of Ly49E by the completely distinct, non-MHC-related protein urokinase plasminogen activator (uPA). uPA is known to be secreted by a variety of cells, including epithelial and hematopoietic cells, and levels are up-regulated during tissue remodeling, infections, and tumorigenesis. Here we show that addition of uPA to Ly49E-positive adult and fetal NK cells inhibits interferon-gamma secretion and reduces their cytotoxic potential, respectively. These uPA-mediated effects are Ly49E-dependent, as they are reversed by addition of anti-Ly49E monoclonal antibody and by down-regulation of Ly49E expression using RNA interference. Our results suggest that uPA, besides its established role in fibrinolysis, tissue remodeling, and tumor metastasis, could be involved in NK cell-mediated immune surveillance and tumor escape.},

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@article{DeSmedt2007,

title = {Notch signaling induces cytoplasmic CD3 epsilon expression in human differentiating NK cells.},

author = {Magda De Smedt and Tom Taghon and Inge Van de Walle and Greet De Smet and Georges Leclercq and Jean Plum},

doi = {10.1182/blood-2007-03-082206},

issn = {0006-4971},

year  = {2007},

date = {2007-10-01},

journal = {Blood},

volume = {110},

pages = {2696--2703},

abstract = {It has been proposed that heterogeneity in natural killer (NK)-cell phenotype and function can be achieved through distinct thymic and bone marrow pathways of NK-cell development. Here, we show a link between Notch signaling and the generation of intracellular CD3epsilon (cyCD3)-expressing NK cells, a cell population that can be detected in vivo. Differentiation of human CD34(+) cord blood progenitors in IL-15-supplemented fetal thymus organ culture or OP9-Delta-like 1 (DL1) coculture resulted in a high percentage of cyCD3(+) NK cells that was blocked by the gamma-secretase inhibitor DAPT. The requirement for Notch signaling to generate cyCD3(+) NK cells was further illustrated by transduction of CD34(+) cord blood (CB) cells with either the active intracellular part of Notch or the dominant-negative mutant of mastermind-like protein 1 that resulted in the generation of NK cells with respectively high or low frequencies of cyCD3. Human thymic CD34(+) progenitor cells displayed the potential to generate cyCD3(+) NK cells, even in the absence of Notch/DL1 signaling. Peripheral blood NK cells were unable to induce cyCD3 expression after DL1 exposure, indicating that Notch-dependent cyCD3 expression can only be achieved during the early phase of NK-cell differentiation.},

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@article{Taghon2007,

title = {Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3.},

author = {Tom Taghon and Mary A Yui and Ellen V Rothenberg},

doi = {10.1038/ni1486},

issn = {1529-2908},

year  = {2007},

date = {2007-08-01},

journal = {Nature immunology},

volume = {8},

pages = {845--855},

abstract = {GATA-3 is essential for T cell development from the earliest stages. However, abundant GATA-3 can drive T lineage precursors to a non-T cell fate, depending on Notch signaling and developmental stage. Here, overexpression of GATA-3 blocked the survival of pro-T cells when Notch-Delta signals were present but enhanced viability in their absence. In fetal thymocytes at the double-negative 1 (DN1) stage and DN2 stage but not those at the DN3 stage, overexpression of GATA-3 rapidly induced respecification to the mast cell lineage with high frequency by direct transcriptional 'reprogramming'. Normal DN2 thymocytes also showed mast cell potential when interleukin 3 and stem cell factor were added in the absence of Notch signaling. Our results suggest a close relationship between the pro-T cell and mast cell programs and a previously unknown function for Notch in T lineage fidelity.},

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pubstate = {ppublish},

tppubtype = {article}

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@article{Smits2007,

title = {Tumor necrosis factor promotes T-cell at the expense of B-cell lymphoid development from cultured human CD34+ cord blood cells.},

author = {Kaatje Smits and Magda De Smedt and Evelien Naessens and Greet De Smet and Veronique Stove and Tom Taghon and Jean Plum and Bruno Verhasselt},

doi = {10.1016/j.exphem.2007.04.009},

issn = {0301-472X},

year  = {2007},

date = {2007-08-01},

journal = {Experimental hematology},

volume = {35},

pages = {1272--1278},

abstract = {Human CD34+ cord blood (CB) cells are hematopoietic progenitors useful for stem cell transplantation, even after ex vivo expansion. We investigated the effect of tumor necrosis factor (TNF) on lymphoid development from cultured CD34+ CB cells. Human CD34+ CB cells were cultured in cytokine mixes with or without TNF. Preculture during 60 hours was followed by in vitro differentiation assays, including fetal thymus organ culture and coculture on murine stromal MS-5 cells. In a next step, experiments were extended to CD34+CD38- and CD34+CD38+ CB cells and prolonged preculture. Preculture in the presence of TNF improved differentiation into T cells and diminished the ability to generate B cells, while NK potential and myeloid development were unaffected. Sorted CD34+CD38- CB cells were more potent T-cell precursors after preculture in TNF, compared to CD34+CD38+ CB cells. In precultured CD34+CD38- CB cells, TNF increased GATA3 but decreased EBF1 expression, in line with the skewed lymphoid differentiation induced by TNF. However, when preculture in the presence of TNF was extended to 1 week, T-cell precursors were lost. After short-term culture of CD34+ CB cells in the presence of TNF, T-cell generation is stimulated at the expense of B-cell generation. T-cell progenitors are enriched in the CD34+CD38- fraction. These results have implications on the culture conditions to be used for CB CD34+ cells prior to transplantation.},

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@article{Tydell2007,

title = {Molecular dissection of prethymic progenitor entry into the T lymphocyte developmental pathway.},

author = {Chace C Tydell and Elizabeth-Sharon David-Fung and Jonathan E Moore and Lee Rowen and Tom Taghon and Ellen V Rothenberg},

doi = {10.4049/jimmunol.179.1.421},

issn = {0022-1767},

year  = {2007},

date = {2007-07-01},

journal = {Journal of immunology (Baltimore, Md. : 1950)},

volume = {179},

pages = {421--438},

abstract = {Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were identified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin(-)Sca-1(+)Kit(+)CD27(-)) and multipotent progenitors (Lin(-)Sca-1(+)Kit(+)CD27(+)), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification. Bcl11b was uniquely T lineage restricted and induced by Notch/Delta signaling specifically upon entry into the T lineage differentiation pathway.},

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@article{Franco2006,

title = {Notch/Delta signaling constrains reengineering of pro-T cells by PU.1.},

author = {Christopher B Franco and Deirdre D Scripture-Adams and Irina Proekt and Tom Taghon and Angela H Weiss and Mary A Yui and Stephanie L Adams and Rochelle A Diamond and Ellen V Rothenberg},

doi = {10.1073/pnas.0601188103},

issn = {0027-8424},

year  = {2006},

date = {2006-08-01},

journal = {Proceedings of the National Academy of Sciences of the United States of America},

volume = {103},

pages = {11993--11998},

abstract = {PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through beta-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo beta-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment.},

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@article{DavidFung2006,

title = {Progression of regulatory gene expression states in fetal and adult pro-T-cell development.},

author = {Elizabeth-Sharon David-Fung and Mary A Yui and Marissa Morales and Hua Wang and Tom Taghon and Rochelle A Diamond and Ellen V Rothenberg},

doi = {10.1111/j.0105-2896.2006.00355.x},

issn = {0105-2896},

year  = {2006},

date = {2006-02-01},

journal = {Immunological reviews},

volume = {209},

pages = {212--236},

abstract = {Precursors entering the T-cell developmental pathway traverse a progression of states characterized by distinctive patterns of gene expression. Of particular interest are regulatory genes, which ultimately control the dwell time of cells in each state and establish the mechanisms that propel them forward to subsequent states. Under particular genetic and developmental circumstances, the transitions between these states occur with different timing, and environmental feedbacks may shift the steady-state accumulations of cells in each state. The fetal transit through pro-T-cell stages is faster than in the adult and subject to somewhat different genetic requirements. To explore causes of such variation, this review presents previously unpublished data on differentiation gene activation in pro-T cells of pre-T-cell receptor-deficient mutant mice and a quantitative comparison of the profiles of transcription factor gene expression in pro-T-cell subsets of fetal and adult wildtype mice. Against a background of consistent gene expression, several regulatory genes show marked differences between fetal and adult expression profiles, including those encoding two basic helix-loop-helix antagonist Id factors, the Ets family factor SpiB and the Notch target gene Deltex1. The results also reveal global differences in regulatory alterations triggered by the first T-cell receptor-dependent selection events in fetal and adult thymopoiesis.},

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@article{Taghon2006,

title = {Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus.},

author = {Tom Taghon and Mary A Yui and Rashmi Pant and Rochelle A Diamond and Ellen V Rothenberg},

doi = {10.1016/j.immuni.2005.11.012},

issn = {1074-7613},

year  = {2006},

date = {2006-01-01},

journal = {Immunity},

volume = {24},

pages = {53--64},

abstract = {The first checkpoint in T cell development, beta selection, has remained incompletely characterized for lack of specific surface markers. We show that CD27 is upregulated in DN3 thymocytes initiating beta selection, concomitant with intracellular TCR-beta expression. Clonal analysis determined that CD27high DN3 cells generate CD4+CD8+ progeny with more than 90% efficiency, faster and more efficiently than the CD27low majority. CD27 upregulation also occurs in gammadelta-selected DN3 thymocytes in TCR-beta-/- mice and in IL2-GFP transgenic reporter mice where GFP marks the earliest emerging TCR-gammadelta cells from DN3 thymocytes. With CD27 to distinguish pre- and postselection DN3 cells, a detailed gene expression analysis defined regulatory changes associated with checkpoint arrest, with beta selection, and with gammadelta selection. gammadelta selection induces higher CD5, Egr, and Runx3 expression as compared to beta selection, but it triggers less proliferation. Our results also reveal differences in Notch/Delta dependence at the earliest stages of divergence between developing alphabeta and gammadelta T-lineage cells.},

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@article{Taghon2005,

title = {Delayed, asynchronous, and reversible T-lineage specification induced by Notch/Delta signaling.},

author = {Tom N Taghon and Elizabeth-Sharon David and Juan Carlos Zúñiga-Pflücker and Ellen V Rothenberg},

doi = {10.1101/gad.1298305},

issn = {0890-9369},

year  = {2005},

date = {2005-04-01},

journal = {Genes & development},

volume = {19},

pages = {965--978},

abstract = {Using the OP9-DL1 system to deliver temporally controlled Notch/Delta signaling, we show that pluripotent hematolymphoid progenitors undergo T-lineage specification and B-lineage inhibition in response to Notch signaling in a delayed and asynchronous way. Highly enriched progenitors from fetal liver require > or =3 d to begin B- or T-lineage differentiation. Clonal switch-culture analysis shows that progeny of some single cells can still generate both B- and T-lineage cells, after 1 wk of continuous delivery or deprivation of Notch/Delta signaling. Notch signaling induces T-cell genes and represses B-cell genes, but kinetics of activation of lineage-specific transcription factors are significantly delayed after induction of Notch target genes and can be temporally uncoupled from the Notch response. In the cells that initiate T-cell differentiation and gene expression most slowly in response to Notch/Delta signaling, Notch target genes are induced to the same level as in the cells that respond most rapidly. Early lineage-specific gene expression is also rapidly reversible in switch cultures. Thus, while necessary to induce and sustain T-cell development, Notch/Delta signaling is not sufficient for T-lineage specification and commitment, but instead can be permissive for the maintenance and proliferation of uncommitted progenitors that are omitted in binary-choice models.},

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@article{Rothenberg2005,

title = {Molecular genetics of T cell development.},

author = {Ellen V Rothenberg and Tom Taghon},

doi = {10.1146/annurev.immunol.23.021704.115737},

issn = {0732-0582},

year  = {2005},

date = {2005-01-01},

journal = {Annual review of immunology},

volume = {23},

pages = {601--649},

abstract = {T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment.},

note = {Grant numbers: NASA NAG2-1588, NSF MCB-9983129.},

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@article{DeSmedt2002,

title = {Active form of Notch imposes T cell fate in human progenitor cells.},

author = {Magda De Smedt and Katia Reynvoet and Tessa Kerre and Tom Taghon and Bruno Verhasselt and Bart Vandekerckhove and Georges Leclercq and Jean Plum},

doi = {10.4049/jimmunol.169.6.3021},

issn = {0022-1767},

year  = {2002},

date = {2002-09-01},

journal = {Journal of immunology (Baltimore, Md. : 1950)},

volume = {169},

pages = {3021--3029},

abstract = {The crucial role of Notch signaling in cell fate decisions in hematopoietic lineage and T lymphocyte development has been well established in mice. Overexpression of the intracellular domain of Notch mediates signal transduction of the protein. By retroviral transduction of this constitutively active truncated intracellular domain in human CD34+ umbilical cord blood progenitor cells, we were able to show that, in coculture with the stromal MS-5 cell line, depending on the cytokines added, the differentiation toward CD19+ B lymphocytes was blocked, the differentiation toward CD14+ monocytes was inhibited, and the differentiation toward CD56+ NK cells was favored. The number of CD7+cyCD3+ cells, a phenotype similar to T/NK progenitor cells, was also markedly increased. In fetal thymus organ culture, transduced CD34+ progenitor cells from umbilical cord blood cells or from thymus consistently generated more TCR-gammadelta T cells, whereas the other T cell subpopulations were largely unaffected. Interestingly, when injected in vivo in SCID-nonobese diabetic mice, the transduced cells generated ectopically human CD4+CD8+ TCR-alphabeta cells in the bone marrow, cells that are normally only present in the thymus, and lacked B cell differentiation potential. Our results show unequivocally that, in human, Notch signaling inhibits the monocyte and B cell fate, promotes the T cell fate, and alters the normal T cell differentiation pathway compatible with a pretumoral state.},

keywords = {},

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tppubtype = {article}

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@article{Taghon2002,

title = {HOX-A10 regulates hematopoietic lineage commitment: evidence for a monocyte-specific transcription factor.},

author = {Tom Taghon and Frank Stolz and Magda De Smedt and Maggy Cnockaert and Bruno Verhasselt and Jean Plum and Georges Leclercq},

doi = {10.1182/blood.v99.4.1197},

issn = {0006-4971},

year  = {2002},

date = {2002-02-01},

journal = {Blood},

volume = {99},

pages = {1197--1204},

abstract = {Homeobox genes are well known for their crucial role during embryogenesis but have also been found to be critically involved in normal and leukemic hematopoiesis. Because most previous studies focused on the role of aberrant HOX gene expression in leukemogenesis and because HOX-A10 is expressed in human CD34(+) precursor cells, this study investigated whether HOX-A10 also plays a pivotal role in normal hematopoietic-lineage determination. The effect of enforced expression of this transcription factor on hematopoietic differentiation of highly purified human cord-blood progenitors was examined by using in vitro assays. In fetal thymic organ cultures, a dramatic reduction in cells expressing high levels of HOX-A10 was observed, along with absence of thymocytes positive for CD3(+) T-cell receptor alphabeta. Furthermore, in MS-5 stromal cell cultures, there was a 7-fold reduction in the number of natural killer cells and a 9-fold reduction in the number of B cells, thus showing a profound defect in differentiation toward the lymphoid lineage in HOX-A10-transduced progenitors. In contrast, the number of CD14(+) monocytic cells in the stromal cell culture was 6-fold higher, suggesting an enhanced differentiation toward the myeloid differentiation pathway of HOX-A10-transduced progenitors. However, there was a slight reduction in the number of CD15(+) granulocytic cells, which were blocked in their final maturation. These data show that HOX-A10 can act as an important key regulator of lineage determination in human hematopoietic progenitor cells.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}