Publications

@article{Unnikrishnan2016,

title = {A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network.},

author = {Ashwin Unnikrishnan and Yi F Guan and Yizhou Huang and Dominik Beck and Julie A I Thoms and Sofie Peirs and Kathy Knezevic and Shiyong Ma and Inge V de Walle and Ineke de Jong and Zara Ali and Ling Zhong and Mark J Raftery and Tom Taghon and Jonas Larsson and Karen L MacKenzie and Pieter Van Vlierberghe and Jason W H Wong and John E Pimanda},

doi = {10.1093/nar/gkw804},

issn = {1362-4962},

year  = {2016},

date = {2016-12-01},

journal = {Nucleic acids research},

volume = {44},

pages = {10644--10661},

abstract = {Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34 haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.},

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}

@article{VanAcker2016,

title = {The role of Ly49E receptor expression on murine intraepithelial lymphocytes in intestinal cancer development and progression.},

author = {Aline Van Acker and Els Louagie and Jessica Filtjens and Sylvie Taveirne and Els Van Ammel and Tessa Kerre and Dirk Elewaut and Tom Taghon and Bart Vandekerckhove and Jean Plum and Georges Leclercq},

doi = {10.1007/s00262-016-1894-6},

issn = {1432-0851},

year  = {2016},

date = {2016-11-01},

journal = {Cancer immunology, immunotherapy : CII},

volume = {65},

pages = {1365--1375},

abstract = {Ly49E is a member of the Ly49 family of NK receptors and is distinct from other members of this family on the basis of its structural properties, expression pattern and ligand recognition. Importantly, Ly49E receptor expression is high on small intestinal and colonic intraepithelial lymphocytes (IELs). Intestinal IELs are regulators of the mucosal immune system and contribute to front-line defense at the mucosal barrier, including anti-tumor immune response. Whereas most Ly49 receptors have MHC class-I ligands, we showed that Ly49E is instead triggered by urokinase plasminogen activator (uPA). uPA has been extensively implicated in tumor development, where increased uPA expression correlates with poor prognosis. As such, we investigated the role of Ly49E receptor expression on intestinal IELs in the anti-tumor immune response. For this purpose, we compared Ly49E wild-type mice to Ly49E knockout mice in two established tumor models: Apc -mediated and azoxymethane-induced intestinal cancer. Our results indicate that Ly49E expression on IELs does not influence the development or progression of intestinal cancer.},

keywords = {},

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}

@article{Drennan2016,

title = {NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20.},

author = {Michael B Drennan and Srinath Govindarajan and Eveline Verheugen and Jonathan M Coquet and Jens Staal and Conor McGuire and Tom Taghon and Georges Leclercq and Rudi Beyaert and Geert van Loo and Bart N Lambrecht and Dirk Elewaut},

doi = {10.1084/jem.20151065},

issn = {1540-9538},

year  = {2016},

date = {2016-09-01},

journal = {The Journal of experimental medicine},

volume = {213},

pages = {1973--1981},

abstract = {Natural killer T (NKT) cells are innate lymphocytes that differentiate into NKT1, NKT2, and NKT17 sublineages during development. However, the signaling events that control NKT sublineage specification and differentiation remain poorly understood. Here, we demonstrate that the ubiquitin-modifying enzyme TNFAIP3/A20, an upstream regulator of T cell receptor (TCR) signaling in T cells, is an essential cell-intrinsic regulator of NKT differentiation. A20 is differentially expressed during NKT cell development, regulates NKT cell maturation, and specifically controls the differentiation and survival of NKT1 and NKT2, but not NKT17, sublineages. Remaining A20-deficient NKT1 and NKT2 thymocytes are hyperactivated in vivo and secrete elevated levels of Th1 and Th2 cytokines after TCR ligation in vitro. Defective NKT development was restored by compound deficiency of MALT1, a key downstream component of TCR signaling in T cells. These findings therefore show that negative regulation of TCR signaling during NKT development controls the differentiation and survival of NKT1 and NKT2 cells.},

keywords = {},

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@article{Filtjens2016a,

title = {Expression of the inhibitory Ly49E receptor is not critically involved in the immune response against cutaneous, pulmonary or liver tumours.},

author = {Jessica Filtjens and Jiri Keirsse and Els Van Ammel and Sylvie Taveirne and Aline Van Acker and Tessa Kerre and Tom Taghon and Bart Vandekerckhove and Jean Plum and Jo A Van Ginderachter and Georges Leclercq},

doi = {10.1038/srep30564},

issn = {2045-2322},

year  = {2016},

date = {2016-07-01},

journal = {Scientific reports},

volume = {6},

pages = {30564},

abstract = {Natural killer (NK) lymphocytes are part of the innate immune system and are important in immune protection against tumourigenesis. NK cells display a broad repertoire of activating and inhibitory cell surface receptors that regulate NK cell activity. The Ly49 family of NK receptors is composed of several members that recognize major histocompatibility complex class I (MHC-I) or MHC-I-related molecules. Ly49E is a unique inhibitory member, being triggered by the non-MHC-I-related protein urokinase plasminogen activator (uPA) in contrast to the known MHC-I-triggering of the other inhibitory Ly49 receptors. Ly49E also has an uncommon expression pattern on NK cells, including high expression on liver DX5(-) NK cells. Furthermore, Ly49E is the only Ly49 member expressed by epidermal γδ T cells. As γδ T cells and/or NK cells have been shown to be involved in the regulation of cutaneous, pulmonary and liver malignancies, and as uPA is involved in tumourigenesis, we investigated the role of the inhibitory Ly49E receptor in the anti-tumour immune response. We demonstrate that, although Ly49E is highly expressed on epidermal γδ T cells and liver NK cells, this receptor does not play a major role in the control of skin tumour formation or in lung and liver tumour development.},

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@article{VandeWalle2016a,

title = {GATA3 induces human T-cell commitment by restraining Notch activity and repressing NK-cell fate.},

author = {Inge Van de Walle and Anne-Catherine Dolens and Kaat Durinck and Katrien De Mulder and Wouter Van Loocke and Sagar Damle and Els Waegemans and Jelle De Medts and Imke Velghe and Magda De Smedt and Bart Vandekerckhove and Tessa Kerre and Jean Plum and Georges Leclercq and Ellen V Rothenberg and Pieter Van Vlierberghe and Frank Speleman and Tom Taghon},

doi = {10.1038/ncomms11171},

issn = {2041-1723},

year  = {2016},

date = {2016-04-01},

journal = {Nature communications},

volume = {7},

pages = {11171},

abstract = {The gradual reprogramming of haematopoietic precursors into the T-cell fate is characterized by at least two sequential developmental stages. Following Notch1-dependent T-cell lineage specification during which the first T-cell lineage genes are expressed and myeloid and dendritic cell potential is lost, T-cell specific transcription factors subsequently induce T-cell commitment by repressing residual natural killer (NK)-cell potential. How these processes are regulated in human is poorly understood, especially since efficient T-cell lineage commitment requires a reduction in Notch signalling activity following T-cell specification. Here, we show that GATA3, in contrast to TCF1, controls human T-cell lineage commitment through direct regulation of three distinct processes: repression of NK-cell fate, upregulation of T-cell lineage genes to promote further differentiation and restraint of Notch activity. Repression of the Notch1 target gene DTX1 hereby is essential to prevent NK-cell differentiation. Thus, GATA3-mediated positive and negative feedback mechanisms control human T-cell lineage commitment.},

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@article{Bogaert2016,

title = {Persistent rotavirus diarrhea post-transplant in a novel JAK3-SCID patient after vaccination.},

author = {Delfien Bogaert and Kristof Van Schil and Tom Taghon and Victoria Bordon and Carolien Bonroy and Melissa Dullaers and Elfride De Baere and Filomeen Haerynck},

doi = {10.1111/pai.12455},

issn = {1399-3038},

year  = {2016},

date = {2016-02-01},

journal = {Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology},

volume = {27},

pages = {93--96},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Engert2016,

title = {The European Hematology Association Roadmap for European Hematology Research: a consensus document.},

author = {Andreas Engert and Carlo Balduini and Anneke Brand and Bertrand Coiffier and Catherine Cordonnier and Hartmut Döhner and Thom Duyvené de Wit and Sabine Eichinger and Willem Fibbe and Tony Green and Fleur de Haas and Achille Iolascon and Thierry Jaffredo and Francesco Rodeghiero and Gilles Salles and Jan Jacob Schuringa and Roadmap E H A for European Hematology Research},

doi = {10.3324/haematol.2015.136739},

issn = {1592-8721},

year  = {2016},

date = {2016-01-01},

journal = {Haematologica},

volume = {101},

pages = {115--208},

abstract = {The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap.The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders.The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.},

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@article{Filtjens2016,

title = {The Ly49E Receptor Inhibits the Immune Control of Acute , jakarta.xml.bind.JAXBElement@a23e762, Infection.},

author = {Jessica Filtjens and Nicolas Coltel and Sabrina Cencig and Sylvie Taveirne and Els Van Ammel and Aline Van Acker and Tessa Kerre and Patrick Matthys and Tom Taghon and Bart Vandekerckhove and Yves Carlier and Carine Truyens and Georges Leclercq},

doi = {10.3389/fimmu.2016.00472},

issn = {1664-3224},

year  = {2016},

date = {2016-01-01},

journal = {Frontiers in immunology},

volume = {7},

pages = {472},

abstract = {The protozoan parasite circulates in the blood upon infection and invades various cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK) and NKT cells play an important role in the immune control of infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA) is induced early upon infection and remains elevated until day 20 post-infection. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT) to Ly49E knockout (KO) mice for their control of experimental infection. Our results show that young, i.e., 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen .},

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pubstate = {epublish},

tppubtype = {article}

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@article{Dolens2016,

title = {Approaches to Study Human T Cell Development.},

author = {Anne-Catherine Dolens and Inge Van de Walle and Tom Taghon},

doi = {10.1007/978-1-4939-2809-5_20},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods in molecular biology (Clifton, N.J.)},

volume = {1323},

pages = {239--251},

abstract = {Not only is human T cell development characterized by unique changes in surface marker expression, but it also requires specific growth factors and conditions to mimic and study T cell development in vitro. In this chapter, we provide an overview of the specific aspects that need attention when performing T cell differentiation cultures with human progenitors.},

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@article{Bonte2016,

title = {Humanized Mice to Study Human T Cell Development.},

author = {Sarah Bonte and Sylvia Snauwaert and Stijn Vanhee and Anne-Catherine Dolens and Tom Taghon and Bart Vandekerckhove and Tessa Kerre},

doi = {10.1007/978-1-4939-2809-5_21},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods in molecular biology (Clifton, N.J.)},

volume = {1323},

pages = {253--272},

abstract = {While in vitro models exist to study human T cell development, they still lack the precise environmental stimuli, such as the exact combination and levels of cytokines and chemokines, that are present in vivo. Moreover, studying the homing of hematopoietic stem (HSC) and progenitor (HPC) cells to the thymus can only be done using in vivo models. Although species-specific differences exist, "humanized" models are generated to circumvent these issues. In this chapter, we focus on the humanized mouse models that can be used to study early T cell development. Models that study solely mature T cells, such as the SCID-PBL (Tary-Lehmann et al., Immunol Today 16:529-533) are therefore not discussed here, but have recently been reviewed (Shultz et al., Nat Rev Immunol 12:786-798).},

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@article{VandeWalle2016,

title = {Characterization and Isolation of Human T Cell Progenitors.},

author = {Inge Van de Walle and Karin Davids and Tom Taghon},

doi = {10.1007/978-1-4939-2809-5_19},

issn = {1940-6029},

year  = {2016},

date = {2016-01-01},

journal = {Methods in molecular biology (Clifton, N.J.)},

volume = {1323},

pages = {221--237},

abstract = {During their development, human T cells undergo similar genomic changes and pass through the same developmental checkpoints as developing thymocytes in the mouse. The difference between both species, however, is that some of these developmental stages are characterized by different phenotypic markers and as a result, evidence emerges that the molecular regulation of human T cell development subtly differs from the mouse [1-4]. In this chapter, we describe in detail how the different stages of human T cell development can be characterized and isolated using specific surface markers.},

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@article{Vanhee2015,

title = {In vitro human embryonic stem cell hematopoiesis mimics MYB-independent yolk sac hematopoiesis.},

author = {Stijn Vanhee and Katrien De Mulder and Yasmine Van Caeneghem and Greet Verstichel and Nadine Van Roy and Björn Menten and Imke Velghe and Jan Philippé and Dominique De Bleser and Bart N Lambrecht and Tom Taghon and Georges Leclercq and Tessa Kerre and Bart Vandekerckhove},

doi = {10.3324/haematol.2014.112144},

issn = {1592-8721},

year  = {2015},

date = {2015-02-01},

journal = {Haematologica},

volume = {100},

pages = {157--166},

abstract = {Although hematopoietic precursor activity can be generated in vitro from human embryonic stem cells, there is no solid evidence for the appearance of multipotent, self-renewing and transplantable hematopoietic stem cells. This could be due to short half-life of hematopoietic stem cells in culture or, alternatively, human embryonic stem cell-initiated hematopoiesis may be hematopoietic stem cell-independent, similar to yolk sac hematopoiesis, generating multipotent progenitors with limited expansion capacity. Since a MYB was reported to be an excellent marker for hematopoietic stem cell-dependent hematopoiesis, we generated a MYB-eGFP reporter human embryonic stem cell line to study formation of hematopoietic progenitor cells in vitro. We found CD34(+) hemogenic endothelial cells rounding up and developing into CD43(+) hematopoietic cells without expression of MYB-eGFP. MYB-eGFP(+) cells appeared relatively late in embryoid body cultures as CD34(+)CD43(+)CD45(-/lo) cells. These MYB-eGFP(+) cells were CD33 positive, proliferated in IL-3 containing media and hematopoietic differentiation was restricted to the granulocytic lineage. In agreement with data obtained on murine Myb(-/-) embryonic stem cells, bright eGFP expression was observed in a subpopulation of cells, during directed myeloid differentiation, which again belonged to the granulocytic lineage. In contrast, CD14(+) macrophage cells were consistently eGFP(-) and were derived from eGFP-precursors only. In summary, no evidence was obtained for in vitro generation of MYB(+) hematopoietic stem cells during embryoid body cultures. The observed MYB expression appeared late in culture and was confined to the granulocytic lineage.},

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@article{VanderMeulen2015,

title = {The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia.},

author = {Joni Van der Meulen and Viraj Sanghvi and Konstantinos Mavrakis and Kaat Durinck and Fang Fang and Filip Matthijssens and Pieter Rondou and Monica Rosen and Tim Pieters and Peter Vandenberghe and Eric Delabesse and Tim Lammens and Barbara De Moerloose and Björn Menten and Nadine Van Roy and Bruno Verhasselt and Bruce Poppe and Yves Benoit and Tom Taghon and Ari M Melnick and Frank Speleman and Hans-Guido Wendel and Pieter Van Vlierberghe},

doi = {10.1182/blood-2014-05-577270},

issn = {1528-0020},

year  = {2015},

date = {2015-01-01},

journal = {Blood},

volume = {125},

pages = {13--21},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive form of leukemia that is mainly diagnosed in children and shows a skewed gender distribution toward males. In this study, we report somatic loss-of-function mutations in the X-linked histone H3K27me3 demethylase ubiquitously transcribed X (UTX) chromosome, in human T-ALL. Interestingly, UTX mutations were exclusively present in male T-ALL patients and allelic expression analysis revealed that UTX escapes X-inactivation in female T-ALL lymphoblasts and normal T cells. Notably, we demonstrate in vitro and in vivo that the H3K27me3 demethylase UTX functions as a bona fide tumor suppressor in T-ALL. Moreover, T-ALL driven by UTX inactivation exhibits collateral sensitivity to pharmacologic H3K27me3 inhibition. All together, our results show how a gender-specific and therapeutically relevant defect in balancing H3K27 methylation contributes to T-cell leukemogenesis.},

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@article{Peirs2015,

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

author = {Sofie Peirs and Joni Van der Meulen and Inge Van de Walle and Tom Taghon and Frank Speleman and Bruce Poppe and Pieter Van Vlierberghe},

doi = {10.1111/imr.12237},

issn = {1600-065X},

year  = {2015},

date = {2015-01-01},

journal = {Immunological reviews},

volume = {263},

pages = {50--67},

abstract = {Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T-ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post-translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL.},

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@article{Goossens2015,

title = {ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.},

author = {Steven Goossens and Enrico Radaelli and Odile Blanchet and Kaat Durinck and Joni Van der Meulen and Sofie Peirs and Tom Taghon and Cedric S Tremblay and Magdaline Costa and Morvarid Farhang Ghahremani and Jelle De Medts and Sonia Bartunkova and Katharina Haigh and Claire Schwab and Natalie Farla and Tim Pieters and Filip Matthijssens and Nadine Van Roy and Adam J Best and Kim Deswarte and Pieter Bogaert and Catherine Carmichael and Adam Rickard and Santi Suryani and Lauryn S Bracken and Raed Alserihi and Kirsten Canté-Barrett and Lieven Haenebalcke and Emmanuelle Clappier and Pieter Rondou and Karolina Slowicka and Danny Huylebroeck and Ananda W Goldrath and Viktor Janzen and Matthew P McCormack and Richard B Lock and David J Curtis and Christine Harrison and Geert Berx and Frank Speleman and Jules P P Meijerink and Jean Soulier and Pieter Van Vlierberghe and Jody J Haigh},

doi = {10.1038/ncomms6794},

issn = {2041-1723},

year  = {2015},

date = {2015-01-01},

journal = {Nature communications},

volume = {6},

pages = {5794},

abstract = {Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model.},

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tppubtype = {article}

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@article{Waegemans2014,

title = {Notch3 activation is sufficient but not required for inducing human T-lineage specification.},

author = {Els Waegemans and Inge Van de Walle and Jelle De Medts and Magda De Smedt and Tessa Kerre and Bart Vandekerckhove and Georges Leclercq and Tao Wang and Jean Plum and Tom Taghon},

doi = {10.4049/jimmunol.1400764},

issn = {1550-6606},

year  = {2014},

date = {2014-12-01},

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

volume = {193},

pages = {5997--6004},

abstract = {Although the role for the individual Notch receptors in early hematopoiesis have been thoroughly investigated in mouse, studies in human have been mostly limited to the use of pan-Notch inhibitors. However, such studies in human are important to predict potential side effects of specific Notch receptor blocking reagents because these are currently being considered as therapeutic tools to treat various Notch-dependent diseases. In this study, we studied the individual roles of Notch1 and Notch3 in early human hematopoietic lineage decisions, particularly during T-lineage specification. Although this process in mice is solely dependent on Notch1 activation, we recently reported Notch3 expression in human uncommitted thymocytes, raising the possibility that Notch3 mediates human T-lineage specification. Although expression of a constitutive activated form of Notch3 (ICN3) results in the induction of T-lineage specification in human CD34(+) hematopoietic progenitor cells, similar to ICN1 overexpression, loss-of-function studies using blocking Abs reveal that only Notch1, but not Notch3, is critical in this process. Blocking of Notch1 activation in OP9-DLL4 cocultures resulted in a complete block in T-lineage specification and induced monocytic and plasmacytoid dendritic cell differentiation instead. In fetal thymus organ cultures, impeded Notch1 activation resulted in B and dendritic cell development. In contrast, Notch3 blocking Abs only marginally affected T-lineage specification and hematopoietic differentiation with a slight increase in monocyte development. No induction of B or dendritic cell development was observed. Thus, our results unambiguously reveal a nonredundant role for Notch1 in human T-lineage specification, despite the expression of other Notch receptors.},

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tppubtype = {article}

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@article{Durinck2014,

title = {The Notch driven long non-coding RNA repertoire in T-cell acute lymphoblastic leukemia.},

author = {Kaat Durinck and Annelynn Wallaert and Inge Van de Walle and Wouter Van Loocke and Pieter-Jan Volders and Suzanne Vanhauwaert and Ellen Geerdens and Yves Benoit and Nadine Van Roy and Bruce Poppe and Jean Soulier and Jan Cools and Pieter Mestdagh and Jo Vandesompele and Pieter Rondou and Pieter Van Vlierberghe and Tom Taghon and Frank Speleman},

doi = {10.3324/haematol.2014.115683},

issn = {1592-8721},

year  = {2014},

date = {2014-12-01},

journal = {Haematologica},

volume = {99},

pages = {1808--1816},

abstract = {Genetic studies in T-cell acute lymphoblastic leukemia have uncovered a remarkable complexity of oncogenic and loss-of-function mutations. Amongst this plethora of genetic changes, NOTCH1 activating mutations stand out as the most frequently occurring genetic defect, identified in more than 50% of T-cell acute lymphoblastic leukemias, supporting a role as an essential driver for this gene in T-cell acute lymphoblastic leukemia oncogenesis. In this study, we aimed to establish a comprehensive compendium of the long non-coding RNA transcriptome under control of Notch signaling. For this purpose, we measured the transcriptional response of all protein coding genes and long non-coding RNAs upon pharmacological Notch inhibition in the human T-cell acute lymphoblastic leukemia cell line CUTLL1 using RNA-sequencing. Similar Notch dependent profiles were established for normal human CD34(+) thymic T-cell progenitors exposed to Notch signaling activity in vivo. In addition, we generated long non-coding RNA expression profiles (array data) from ex vivo isolated Notch active CD34(+) and Notch inactive CD4(+)CD8(+) thymocytes and from a primary cohort of 15 T-cell acute lymphoblastic leukemia patients with known NOTCH1 mutation status. Integration of these expression datasets with publicly available Notch1 ChIP-sequencing data resulted in the identification of long non-coding RNAs directly regulated by Notch activity in normal and malignant T cells. Given the central role of Notch in T-cell acute lymphoblastic leukemia oncogenesis, these data pave the way for the development of novel therapeutic strategies that target hyperactive Notch signaling in human T-cell acute lymphoblastic leukemia.},

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@article{Peirs2014,

title = {ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.},

author = {Sofie Peirs and Filip Matthijssens and Steven Goossens and Inge Van de Walle and Katia Ruggero and Charles E de Bock and Sandrine Degryse and Kirsten Canté-Barrett and Delphine Briot and Emmanuelle Clappier and Tim Lammens and Barbara De Moerloose and Yves Benoit and Bruce Poppe and Jules P Meijerink and Jan Cools and Jean Soulier and Terence H Rabbitts and Tom Taghon and Frank Speleman and Pieter Van Vlierberghe},

doi = {10.1182/blood-2014-05-574566},

issn = {1528-0020},

year  = {2014},

date = {2014-12-01},

journal = {Blood},

volume = {124},

pages = {3738--3747},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in human T-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Sanghvi2014,

title = {Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia.},

author = {Viraj R Sanghvi and Konstantinos J Mavrakis and Joni Van der Meulen and Michael Boice and Andrew L Wolfe and Mark Carty and Prathibha Mohan and Pieter Rondou and Nicholas D Socci and Yves Benoit and Tom Taghon and Pieter Van Vlierberghe and Christina S Leslie and Frank Speleman and Hans-Guido Wendel},

doi = {10.1126/scisignal.2005500},

issn = {1937-9145},

year  = {2014},

date = {2014-11-01},

journal = {Science signaling},

volume = {7},

pages = {ra111},

abstract = {The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Mets2014,

title = {MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia.},

author = {Evelien Mets and Gert Van Peer and Joni Van der Meulen and Michael Boice and Tom Taghon and Steven Goossens and Pieter Mestdagh and Yves Benoit and Barbara De Moerloose and Nadine Van Roy and Bruce Poppe and Jo Vandesompele and Hans-Guido Wendel and Pieter Van Vlierberghe and Frank Speleman and Pieter Rondou},

doi = {10.3324/haematol.2013.099515},

issn = {1592-8721},

year  = {2014},

date = {2014-08-01},

journal = {Haematologica},

volume = {99},

pages = {1326--1333},

abstract = {T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3'UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}