Publications
2020
Lavaert, Marieke; Liang, Kai Ling; Vandamme, Niels; Park, Jong-Eun; Roels, Juliette; Kowalczyk, Monica S; Li, Bo; Ashenberg, Orr; Tabaka, Marcin; Dionne, Danielle; Tickle, Timothy L; Slyper, Michal; Rozenblatt-Rosen, Orit; Vandekerckhove, Bart; Leclercq, Georges; Regev, Aviv; Vlierberghe, Pieter Van; Guilliams, Martin; Teichmann, Sarah A; Saeys, Yvan; Taghon, Tom
Integrated scRNA-Seq Identifies Human Postnatal Thymus Seeding Progenitors and Regulatory Dynamics of Differentiating Immature Thymocytes. Journal Article
In: Immunity, vol. 52, pp. 1088–1104.e6, 2020, ISSN: 1097-4180.
@article{Lavaert2020a,
title = {Integrated scRNA-Seq Identifies Human Postnatal Thymus Seeding Progenitors and Regulatory Dynamics of Differentiating Immature Thymocytes.},
author = {Marieke Lavaert and Kai Ling Liang and Niels Vandamme and Jong-Eun Park and Juliette Roels and Monica S Kowalczyk and Bo Li and Orr Ashenberg and Marcin Tabaka and Danielle Dionne and Timothy L Tickle and Michal Slyper and Orit Rozenblatt-Rosen and Bart Vandekerckhove and Georges Leclercq and Aviv Regev and Pieter Van Vlierberghe and Martin Guilliams and Sarah A Teichmann and Yvan Saeys and Tom Taghon},
doi = {10.1016/j.immuni.2020.03.019},
issn = {1097-4180},
year = {2020},
date = {2020-01-01},
journal = {Immunity},
volume = {52},
pages = {1088--1104.e6},
abstract = {During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone-marrow-derived hematopoietic progenitors that migrate through the bloodstream. The current understanding of the nature of thymic immigrants is largely based on data from pre-clinical models. Here, we employed single-cell RNA sequencing (scRNA-seq) to examine the immature postnatal thymocyte population in humans. Integration of bone marrow and peripheral blood precursor datasets identified two putative thymus seeding progenitors that varied in expression of CD7; CD10; and the homing receptors CCR7, CCR9, and ITGB7. Whereas both precursors supported T cell development, only one contributed to intrathymic dendritic cell (DC) differentiation, predominantly of plasmacytoid dendritic cells. Trajectory inference delineated the transcriptional dynamics underlying early human T lineage development, enabling prediction of transcription factor (TF) modules that drive stage-specific steps of human T cell development. This comprehensive dataset defines the expression signature of immature human thymocytes and provides a resource for the further study of human thymopoiesis.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone-marrow-derived hematopoietic progenitors that migrate through the bloodstream. The current understanding of the nature of thymic immigrants is largely based on data from pre-clinical models. Here, we employed single-cell RNA sequencing (scRNA-seq) to examine the immature postnatal thymocyte population in humans. Integration of bone marrow and peripheral blood precursor datasets identified two putative thymus seeding progenitors that varied in expression of CD7; CD10; and the homing receptors CCR7, CCR9, and ITGB7. Whereas both precursors supported T cell development, only one contributed to intrathymic dendritic cell (DC) differentiation, predominantly of plasmacytoid dendritic cells. Trajectory inference delineated the transcriptional dynamics underlying early human T lineage development, enabling prediction of transcription factor (TF) modules that drive stage-specific steps of human T cell development. This comprehensive dataset defines the expression signature of immature human thymocytes and provides a resource for the further study of human thymopoiesis.
Roels, Juliette; Kuchmiy, Anna; Decker, Matthias De; Strubbe, Steven; Lavaert, Marieke; Liang, Kai Ling; Leclercq, Georges; Vandekerckhove, Bart; Nieuwerburgh, Filip Van; Vlierberghe, Pieter Van; Taghon, Tom
Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development. Journal Article
In: Nature immunology, vol. 21, pp. 1280–1292, 2020, ISSN: 1529-2916.
@article{Roels2020a,
title = {Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development.},
author = {Juliette Roels and Anna Kuchmiy and Matthias De Decker and Steven Strubbe and Marieke Lavaert and Kai Ling Liang and Georges Leclercq and Bart Vandekerckhove and Filip Van Nieuwerburgh and Pieter Van Vlierberghe and Tom Taghon},
doi = {10.1038/s41590-020-0747-9},
issn = {1529-2916},
year = {2020},
date = {2020-01-01},
journal = {Nature immunology},
volume = {21},
pages = {1280--1292},
abstract = {The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3- and BCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4 and CD8 αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC-sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3- and BCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4 and CD8 αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development.
Drobna, Monika; Szarzyńska, Bronisława; Jaksik, Roman; Sędek, Łukasz; Kuchmiy, Anna; Taghon, Tom; Vlierberghe, Pieter Van; Szczepański, Tomasz; Witt, Michał; Dawidowska, Małgorzata
hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro Journal Article
In: Cells, vol. 9, 2020, ISSN: 2073-4409.
@article{Drobna2020,
title = {hsa-miR-20b-5p and hsa-miR-363-3p Affect Expression of PTEN and BIM Tumor Suppressor Genes and Modulate Survival of T-ALL Cells In Vitro},
author = {Monika Drobna and Bronisława Szarzyńska and Roman Jaksik and Łukasz Sędek and Anna Kuchmiy and Tom Taghon and Pieter Van Vlierberghe and Tomasz Szczepański and Michał Witt and Małgorzata Dawidowska},
doi = {10.3390/cells9051137},
issn = {2073-4409},
year = {2020},
date = {2020-01-01},
journal = {Cells},
volume = {9},
abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy arising from T lymphocyte precursors. We have previously shown by miRNA-seq, that miRNAs from the mir-106a-363 cluster are overexpressed in pediatric T-ALL. In silico analysis indicated their potential involvement in the regulation of apoptosis. Here, we aimed to test the hypothesis on the pro-tumorigenic roles of these miRNAs in T-ALL cells in vitro. We demonstrate, for the first time, that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster, when upregulated in T-ALL cells in vitro, protect leukemic cells from apoptosis, enhance proliferation, and contribute to growth advantage. We show, using dual luciferase reporter assays, Ago2-RNA immunoprecipitation, RT-qPCR, and Western blots, that the oncogenic effects of these upregulated miRNAs might, at least in part, be mediated by the downregulation of two important tumor suppressor genes, and , targeted by both miRNAs. Additionally, we demonstrate the cooperative effects of these two miRNAs by simultaneous inhibition of both miRNAs as compared to the inhibition of single miRNAs. We postulate that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster might serve as oncomiRs in T-ALL, by contributing to post-transcriptional repression of key tumor suppressors, and .},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy arising from T lymphocyte precursors. We have previously shown by miRNA-seq, that miRNAs from the mir-106a-363 cluster are overexpressed in pediatric T-ALL. In silico analysis indicated their potential involvement in the regulation of apoptosis. Here, we aimed to test the hypothesis on the pro-tumorigenic roles of these miRNAs in T-ALL cells in vitro. We demonstrate, for the first time, that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster, when upregulated in T-ALL cells in vitro, protect leukemic cells from apoptosis, enhance proliferation, and contribute to growth advantage. We show, using dual luciferase reporter assays, Ago2-RNA immunoprecipitation, RT-qPCR, and Western blots, that the oncogenic effects of these upregulated miRNAs might, at least in part, be mediated by the downregulation of two important tumor suppressor genes, and , targeted by both miRNAs. Additionally, we demonstrate the cooperative effects of these two miRNAs by simultaneous inhibition of both miRNAs as compared to the inhibition of single miRNAs. We postulate that hsa-miR-20b-5p and hsa-miR-363-3p from the mir-106a-363 cluster might serve as oncomiRs in T-ALL, by contributing to post-transcriptional repression of key tumor suppressors, and .
Bonte, Sarah; Munter, Stijn De; Goetgeluk, Glenn; Ingels, Joline; Pille, Melissa; Billiet, Lore; Taghon, Tom; Leclercq, Georges; Vandekerckhove, Bart; Kerre, Tessa
T-cells with a single tumor antigen-specific T-cell receptor can be generated in vitro from clinically relevant stem cell sources Journal Article
In: Oncoimmunology, vol. 9, pp. 1727078, 2020, ISSN: 2162-4011.
@article{Bonte2020,
title = {T-cells with a single tumor antigen-specific T-cell receptor can be generated in vitro from clinically relevant stem cell sources},
author = {Sarah Bonte and Stijn De Munter and Glenn Goetgeluk and Joline Ingels and Melissa Pille and Lore Billiet and Tom Taghon and Georges Leclercq and Bart Vandekerckhove and Tessa Kerre},
doi = {10.1080/2162402X.2020.1727078},
issn = {2162-4011},
year = {2020},
date = {2020-01-01},
journal = {Oncoimmunology},
volume = {9},
pages = {1727078},
abstract = {Chimeric antigen receptor (CAR) T-cells have shown great promise in the treatment of B-cell malignancies. For acute myeloid leukemia (AML), however, the optimal target surface antigen has yet to be discovered. Alternatively, T-cell receptor (TCR)-redirected T-cells target intracellular antigens, marking a broader territory of available target antigens. Currently, adoptive TCR T-cell therapy uses peripheral blood lymphocytes for the introduction of a transgenic TCR. However, this can cause graft-versus-host disease, due to mispairing of introduced and endogenous TCR chains. Therefore, we started from hematopoietic stem and progenitor cells (HSPC), that do not express a TCR yet, isolated from healthy donors, patients in remission after chemotherapy and AML patients at diagnosis. Using the OP9-DL1 in vitro co-culture system and agonist selection, TCR-transduced HSPC develop into mature tumor antigen-specific T-cells with only one TCR. We show here that this approach is feasible with adult HSPC from clinically relevant sources, albeit with slower maturation and lower cell yield compared to cord blood HSPC. Moreover, cryopreservation of HSPC does not have an effect on cell numbers or functionality of the generated T-cells. In conclusion, we show here that it is feasible to generate TA-specific T-cells from HSPC from adult healthy donors and patients and we believe these T-cells could be of use as a very valuable form of patient-tailored T-cell immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chimeric antigen receptor (CAR) T-cells have shown great promise in the treatment of B-cell malignancies. For acute myeloid leukemia (AML), however, the optimal target surface antigen has yet to be discovered. Alternatively, T-cell receptor (TCR)-redirected T-cells target intracellular antigens, marking a broader territory of available target antigens. Currently, adoptive TCR T-cell therapy uses peripheral blood lymphocytes for the introduction of a transgenic TCR. However, this can cause graft-versus-host disease, due to mispairing of introduced and endogenous TCR chains. Therefore, we started from hematopoietic stem and progenitor cells (HSPC), that do not express a TCR yet, isolated from healthy donors, patients in remission after chemotherapy and AML patients at diagnosis. Using the OP9-DL1 in vitro co-culture system and agonist selection, TCR-transduced HSPC develop into mature tumor antigen-specific T-cells with only one TCR. We show here that this approach is feasible with adult HSPC from clinically relevant sources, albeit with slower maturation and lower cell yield compared to cord blood HSPC. Moreover, cryopreservation of HSPC does not have an effect on cell numbers or functionality of the generated T-cells. In conclusion, we show here that it is feasible to generate TA-specific T-cells from HSPC from adult healthy donors and patients and we believe these T-cells could be of use as a very valuable form of patient-tailored T-cell immunotherapy.
Munter, Stijn De; Parys, Alexander Van; Bral, Layla; Ingels, Joline; Goetgeluk, Glenn; Bonte, Sarah; Pille, Melissa; Billiet, Lore; Weening, Karin; Verhee, Annick; der Heyden, Jose Van; Taghon, Tom; Leclercq, Georges; Kerre, Tessa; Tavernier, Jan; Vandekerckhove, Bart
Rapid and Effective Generation of Nanobody Based CARs using PCR and Gibson Assembly. Journal Article
In: International journal of molecular sciences, vol. 21, 2020, ISSN: 1422-0067.
@article{DeMunter2020,
title = {Rapid and Effective Generation of Nanobody Based CARs using PCR and Gibson Assembly.},
author = {Stijn De Munter and Alexander Van Parys and Layla Bral and Joline Ingels and Glenn Goetgeluk and Sarah Bonte and Melissa Pille and Lore Billiet and Karin Weening and Annick Verhee and Jose Van der Heyden and Tom Taghon and Georges Leclercq and Tessa Kerre and Jan Tavernier and Bart Vandekerckhove},
doi = {10.3390/ijms21030883},
issn = {1422-0067},
year = {2020},
date = {2020-01-01},
journal = {International journal of molecular sciences},
volume = {21},
abstract = {Recent approval of chimeric antigen receptor (CAR) T cell therapy by the European Medicines Agency (EMA)/Federal and Drug Administration (FDA) and the remarkable results of CAR T clinical trials illustrate the curative potential of this therapy. While CARs against a multitude of different antigens are being developed and tested (pre)clinically, there is still a need for optimization. The use of single-chain variable fragments (scFvs) as targeting moieties hampers the quick generation of functional CARs and could potentially limit the efficacy. Instead, nanobodies may largely circumvent these difficulties. We used an available nanobody library generated after immunization of llamas against Cluster of Differentiation (CD) 20 through DNA vaccination or against the ectodomain of CD33 using soluble protein. The nanobody specific sequences were amplified by PCR and cloned by Gibson Assembly into a retroviral vector containing two different second-generation CAR constructs. After transduction in T cells, we observed high cell membrane nanoCAR expression in all cases. Following stimulation of nanoCAR-expressing T cells with antigen-positive cell lines, robust T cell activation, cytokine production and tumor cell lysis both in vitro and in vivo was observed. The use of nanobody technology in combination with PCR and Gibson Assembly allows for the rapid and effective generation of compact CARs.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Recent approval of chimeric antigen receptor (CAR) T cell therapy by the European Medicines Agency (EMA)/Federal and Drug Administration (FDA) and the remarkable results of CAR T clinical trials illustrate the curative potential of this therapy. While CARs against a multitude of different antigens are being developed and tested (pre)clinically, there is still a need for optimization. The use of single-chain variable fragments (scFvs) as targeting moieties hampers the quick generation of functional CARs and could potentially limit the efficacy. Instead, nanobodies may largely circumvent these difficulties. We used an available nanobody library generated after immunization of llamas against Cluster of Differentiation (CD) 20 through DNA vaccination or against the ectodomain of CD33 using soluble protein. The nanobody specific sequences were amplified by PCR and cloned by Gibson Assembly into a retroviral vector containing two different second-generation CAR constructs. After transduction in T cells, we observed high cell membrane nanoCAR expression in all cases. Following stimulation of nanoCAR-expressing T cells with antigen-positive cell lines, robust T cell activation, cytokine production and tumor cell lysis both in vitro and in vivo was observed. The use of nanobody technology in combination with PCR and Gibson Assembly allows for the rapid and effective generation of compact CARs.
2019
Coninck, Stien De; Berx, Geert; Taghon, Tom; Vlierberghe, Pieter Van; Goossens, Steven
ZEB2 in T-cells and T-ALL. Journal Article
In: Advances in biological regulation, vol. 74, pp. 100639, 2019, ISSN: 2212-4934.
@article{DeConinck2019,
title = {ZEB2 in T-cells and T-ALL.},
author = {Stien De Coninck and Geert Berx and Tom Taghon and Pieter Van Vlierberghe and Steven Goossens},
doi = {10.1016/j.jbior.2019.100639},
issn = {2212-4934},
year = {2019},
date = {2019-12-01},
journal = {Advances in biological regulation},
volume = {74},
pages = {100639},
abstract = {The identification of the rare but recurrent t(2; 14)(q22; q32) translocation involving the ZEB2 locus in T-cell acute lymphoblastic leukemia, suggested that ZEB2 is an oncogenic driver of this high-risk subtype of leukemia. ZEB2, a zinc finger E-box homeobox binding transcription factor, is a master regulator of cellular plasticity and its expression is correlated with poor overall survival of cancer patients. Recent loss- and gain-of-function in the mouse revealed important roles of ZEB2 during different stages of hematopoiesis, including the T-cell lineage. Here, we summarize the roles of ZEB2 in T-cells, their development, and malignant transformation to T-ALL.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
The identification of the rare but recurrent t(2; 14)(q22; q32) translocation involving the ZEB2 locus in T-cell acute lymphoblastic leukemia, suggested that ZEB2 is an oncogenic driver of this high-risk subtype of leukemia. ZEB2, a zinc finger E-box homeobox binding transcription factor, is a master regulator of cellular plasticity and its expression is correlated with poor overall survival of cancer patients. Recent loss- and gain-of-function in the mouse revealed important roles of ZEB2 during different stages of hematopoiesis, including the T-cell lineage. Here, we summarize the roles of ZEB2 in T-cells, their development, and malignant transformation to T-ALL.
Bonnardel, Johnny; T'Jonck, Wouter; Gaublomme, Djoere; Browaeys, Robin; Scott, Charlotte L; Martens, Liesbet; Vanneste, Bavo; Prijck, Sofie De; Nedospasov, Sergei A; Kremer, Anna; Hamme, Evelien Van; Borghgraef, Peter; Toussaint, Wendy; Bleser, Pieter De; Mannaerts, Inge; Beschin, Alain; van Grunsven, Leo A; Lambrecht, Bart N; Taghon, Tom; Lippens, Saskia; Elewaut, Dirk; Saeys, Yvan; Guilliams, Martin
Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche. Journal Article
In: Immunity, vol. 51, pp. 638–654.e9, 2019, ISSN: 1097-4180.
@article{Bonnardel2019,
title = {Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche.},
author = {Johnny Bonnardel and Wouter T'Jonck and Djoere Gaublomme and Robin Browaeys and Charlotte L Scott and Liesbet Martens and Bavo Vanneste and Sofie De Prijck and Sergei A Nedospasov and Anna Kremer and Evelien Van Hamme and Peter Borghgraef and Wendy Toussaint and Pieter De Bleser and Inge Mannaerts and Alain Beschin and Leo A van Grunsven and Bart N Lambrecht and Tom Taghon and Saskia Lippens and Dirk Elewaut and Yvan Saeys and Martin Guilliams},
doi = {10.1016/j.immuni.2019.08.017},
issn = {1097-4180},
year = {2019},
date = {2019-10-01},
journal = {Immunity},
volume = {51},
pages = {638--654.e9},
abstract = {Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.
de Bock, Charles E; Down, Michelle; Baidya, Kinsha; Sweron, Bram; Boyd, Andrew W; Fiers, Mark; Burns, Gordon F; Molloy, Timothy J; Lock, Richard B; Soulier, Jean; Taghon, Tom; Vlierberghe, Pieter Van; Cools, Jan; Holst, Jeff; Thorne, Rick F
T-cell acute lymphoblastic leukemias express a unique truncated FAT1 isoform that cooperates with NOTCH1 in leukemia development. Journal Article
In: Haematologica, vol. 104, pp. e204–e207, 2019, ISSN: 1592-8721.
@article{Bock2019,
title = {T-cell acute lymphoblastic leukemias express a unique truncated FAT1 isoform that cooperates with NOTCH1 in leukemia development.},
author = {Charles E de Bock and Michelle Down and Kinsha Baidya and Bram Sweron and Andrew W Boyd and Mark Fiers and Gordon F Burns and Timothy J Molloy and Richard B Lock and Jean Soulier and Tom Taghon and Pieter Van Vlierberghe and Jan Cools and Jeff Holst and Rick F Thorne},
doi = {10.3324/haematol.2018.198424},
issn = {1592-8721},
year = {2019},
date = {2019-05-01},
journal = {Haematologica},
volume = {104},
pages = {e204--e207},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Habets, Roger A; de Bock, Charles E; Serneels, Lutgarde; Lodewijckx, Inge; Verbeke, Delphine; Nittner, David; Narlawar, Rajeshwar; Demeyer, Sofie; Dooley, James; Liston, Adrian; Taghon, Tom; Cools, Jan; de Strooper, Bart
Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Journal Article
In: Science translational medicine, vol. 11, 2019, ISSN: 1946-6242.
@article{Habets2019,
title = {Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition.},
author = {Roger A Habets and Charles E de Bock and Lutgarde Serneels and Inge Lodewijckx and Delphine Verbeke and David Nittner and Rajeshwar Narlawar and Sofie Demeyer and James Dooley and Adrian Liston and Tom Taghon and Jan Cools and Bart de Strooper},
doi = {10.1126/scitranslmed.aau6246},
issn = {1946-6242},
year = {2019},
date = {2019-05-01},
journal = {Science translational medicine},
volume = {11},
abstract = {Given the high frequency of activating mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Given the high frequency of activating mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.
Goossens, Steven; Wang, Jueqiong; Tremblay, Cedric S; Medts, Jelle De; T'Sas, Sara; Nguyen, Thao; Saw, Jesslyn; Haigh, Katharina; Curtis, David J; Vlierberghe, Pieter Van; Berx, Geert; Taghon, Tom; Haigh, Jody J
ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms. Journal Article
In: Haematologica, vol. 104, pp. 1608–1616, 2019, ISSN: 1592-8721.
@article{Goossens2019,
title = {ZEB2 and LMO2 drive immature T-cell lymphoblastic leukemia via distinct oncogenic mechanisms.},
author = {Steven Goossens and Jueqiong Wang and Cedric S Tremblay and Jelle De Medts and Sara T'Sas and Thao Nguyen and Jesslyn Saw and Katharina Haigh and David J Curtis and Pieter Van Vlierberghe and Geert Berx and Tom Taghon and Jody J Haigh},
doi = {10.3324/haematol.2018.207837},
issn = {1592-8721},
year = {2019},
date = {2019-01-01},
journal = {Haematologica},
volume = {104},
pages = {1608--1616},
abstract = {ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and resistance to therapy. Using conditional loss-of-function mice, we previously demonstrated that also plays pivotal roles in hematopoiesis, controlling important cell fate decisions, lineage commitment and fidelity. In addition, upon Zeb2 overexpression, mice spontaneously develop immature T-cell lymphoblastic leukemia. Here we show that pre-leukemic -overexpressing thymocytes are characterized by a differentiation delay at beta-selection due to aberrant activation of the interleukin-7 receptor signaling pathway. Notably, and in contrast to Lmo2-overexpressing thymocytes, these pre-leukemic -overexpressing T-cell progenitors display no acquired self-renewal properties. Finally, activation in more differentiated T-cell precursor cells can also drive malignant T-cell development, suggesting that the early T-cell differentiation delay is not essential for -mediated leukemic transformation. Altogether, our data suggest that and drive malignant transformation of immature T-cell progenitors via distinct molecular mechanisms.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
ZEB1 and ZEB2 are structurally related E-box binding homeobox transcription factors that induce epithelial to mesenchymal transitions during development and disease. As such, they regulate cancer cell invasion, dissemination and metastasis of solid tumors. In addition, their expression is associated with the gain of cancer stem cell properties and resistance to therapy. Using conditional loss-of-function mice, we previously demonstrated that also plays pivotal roles in hematopoiesis, controlling important cell fate decisions, lineage commitment and fidelity. In addition, upon Zeb2 overexpression, mice spontaneously develop immature T-cell lymphoblastic leukemia. Here we show that pre-leukemic -overexpressing thymocytes are characterized by a differentiation delay at beta-selection due to aberrant activation of the interleukin-7 receptor signaling pathway. Notably, and in contrast to Lmo2-overexpressing thymocytes, these pre-leukemic -overexpressing T-cell progenitors display no acquired self-renewal properties. Finally, activation in more differentiated T-cell precursor cells can also drive malignant T-cell development, suggesting that the early T-cell differentiation delay is not essential for -mediated leukemic transformation. Altogether, our data suggest that and drive malignant transformation of immature T-cell progenitors via distinct molecular mechanisms.
2018
Verboom, Karen; Loocke, Wouter Van; Volders, Pieter-Jan; Decaesteker, Bieke; Cobos, Francisco Avila; Bornschein, Simon; de Bock, Charles E; Atak, Zeynep Kalender; Clappier, Emmanuelle; Aerts, Stein; Cools, Jan; Soulier, Jean; Taghon, Tom; Vlierberghe, Pieter Van; Vandesompele, Jo; Speleman, Frank; Durinck, Kaat
In: Haematologica, vol. 103, pp. e585–e589, 2018, ISSN: 1592-8721.
@article{Verboom2018,
title = {A comprehensive inventory of TLX1 controlled long non-coding RNAs in T-cell acute lymphoblastic leukemia through polyA+ and total RNA sequencing.},
author = {Karen Verboom and Wouter Van Loocke and Pieter-Jan Volders and Bieke Decaesteker and Francisco Avila Cobos and Simon Bornschein and Charles E de Bock and Zeynep Kalender Atak and Emmanuelle Clappier and Stein Aerts and Jan Cools and Jean Soulier and Tom Taghon and Pieter Van Vlierberghe and Jo Vandesompele and Frank Speleman and Kaat Durinck},
doi = {10.3324/haematol.2018.190587},
issn = {1592-8721},
year = {2018},
date = {2018-12-01},
journal = {Haematologica},
volume = {103},
pages = {e585--e589},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Gachet, Stéphanie; El-Chaar, Tiama; Avran, David; Genesca, Eulalia; Catez, Frédéric; Quentin, Samuel; Delord, Marc; Thérizols, Gabriel; Briot, Delphine; Meunier, Godelieve; Hernandez, Lucie; Pla, Marika; Smits, Willem K; Buijs-Gladdines, Jessica G; Loocke, Wouter Van; Menschaert, Gerben; André-Schmutz, Isabelle; Taghon, Tom; Vlierberghe, Pieter Van; Meijerink, Jules P; Baruchel, André; Dombret, Hervé; Clappier, Emmanuelle; Diaz, Jean-Jacques; Gazin, Claude; de Thé, Hugues; Sigaux, François; Soulier, Jean
Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation. Journal Article
In: Cancer discovery, vol. 8, pp. 1614–1631, 2018, ISSN: 2159-8290.
@article{Gachet2018,
title = {Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.},
author = {Stéphanie Gachet and Tiama El-Chaar and David Avran and Eulalia Genesca and Frédéric Catez and Samuel Quentin and Marc Delord and Gabriel Thérizols and Delphine Briot and Godelieve Meunier and Lucie Hernandez and Marika Pla and Willem K Smits and Jessica G Buijs-Gladdines and Wouter Van Loocke and Gerben Menschaert and Isabelle André-Schmutz and Tom Taghon and Pieter Van Vlierberghe and Jules P Meijerink and André Baruchel and Hervé Dombret and Emmanuelle Clappier and Jean-Jacques Diaz and Claude Gazin and Hugues de Thé and François Sigaux and Jean Soulier},
doi = {10.1158/2159-8290.CD-17-0831},
issn = {2159-8290},
year = {2018},
date = {2018-12-01},
journal = {Cancer discovery},
volume = {8},
pages = {1614--1631},
abstract = {Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, (encoding hnRNP-Q) and (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a -driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of and Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention. .},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, (encoding hnRNP-Q) and (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a -driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of and Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention. .
Su, Hexiu; Hu, Juncheng; Huang, Liang; Yang, Yang; Thenoz, Morgan; Kuchmiy, Anna; Hu, Yufeng; Li, Peng; Feng, Hui; Zhou, Yu; Taghon, Tom; Vlierberghe, Pieter Van; Qing, Guoliang; Chen, Zhichao; Liu, Hudan
SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival. Journal Article
In: Nature communications, vol. 9, pp. 4281, 2018, ISSN: 2041-1723.
@article{Su2018,
title = {SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival.},
author = {Hexiu Su and Juncheng Hu and Liang Huang and Yang Yang and Morgan Thenoz and Anna Kuchmiy and Yufeng Hu and Peng Li and Hui Feng and Yu Zhou and Tom Taghon and Pieter Van Vlierberghe and Guoliang Qing and Zhichao Chen and Hudan Liu},
doi = {10.1038/s41467-018-06523-4},
issn = {2041-1723},
year = {2018},
date = {2018-10-01},
journal = {Nature communications},
volume = {9},
pages = {4281},
abstract = {T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1-SHQ1-MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression significantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1-SHQ1-MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation.
Simons, Laura; Ma, Kuiying; de Chappedelaine, Corinne; Moiranghtem, Ranjita Devi; Elkaim, Elodie; Olivré, Juliette; Susini, Sandrine; Appourchaux, Kevin; Reimann, Christian; Sadek, Hanem; Pellé, Olivier; Cagnard, Nicolas; Magrin, Elisa; Lagresle-Peyrou, Chantal; Taghon, Tom; Rausell, Antonio; Cavazzana, Marina; André-Schmutz, Isabelle
Generation of adult human T-cell progenitors for immunotherapeutic applications. Journal Article
In: The Journal of allergy and clinical immunology, vol. 141, pp. 1491–1494.e4, 2018, ISSN: 1097-6825.
@article{Simons2018,
title = {Generation of adult human T-cell progenitors for immunotherapeutic applications.},
author = {Laura Simons and Kuiying Ma and Corinne de Chappedelaine and Ranjita Devi Moiranghtem and Elodie Elkaim and Juliette Olivré and Sandrine Susini and Kevin Appourchaux and Christian Reimann and Hanem Sadek and Olivier Pellé and Nicolas Cagnard and Elisa Magrin and Chantal Lagresle-Peyrou and Tom Taghon and Antonio Rausell and Marina Cavazzana and Isabelle André-Schmutz},
doi = {10.1016/j.jaci.2017.10.034},
issn = {1097-6825},
year = {2018},
date = {2018-01-01},
journal = {The Journal of allergy and clinical immunology},
volume = {141},
pages = {1491--1494.e4},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
2017
Wallaert, Annelynn; Loocke, Wouter Van; Hernandez, Lucie; Taghon, Tom; Speleman, Frank; Vlierberghe, Pieter Van
Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing. Journal Article
In: Scientific reports, vol. 7, pp. 7901, 2017, ISSN: 2045-2322.
@article{Wallaert2017,
title = {Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing.},
author = {Annelynn Wallaert and Wouter Van Loocke and Lucie Hernandez and Tom Taghon and Frank Speleman and Pieter Van Vlierberghe},
doi = {10.1038/s41598-017-08148-x},
issn = {2045-2322},
year = {2017},
date = {2017-08-01},
journal = {Scientific reports},
volume = {7},
pages = {7901},
abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that can be classified into different molecular genetic subtypes according to their mRNA gene expression profile. In this study, we applied RNA sequencing to investigate the full spectrum of miRNA expression in primary T-ALL patient samples, T-ALL leukemia cell lines and healthy donor thymocytes. Notably, this analysis revealed that genetic subtypes of human T-ALL also display unique miRNA expression signatures, which are largely conserved in human T-ALL cell lines with corresponding genetic background. Furthermore, small RNA-sequencing also unraveled the variety of isoforms that are expressed for each miRNA in T-ALL and showed that a significant number of miRNAs are actually represented by an alternative isomiR. Finally, comparison of CD34 and CD4 CD8 healthy donor thymocytes and T-ALL miRNA profiles allowed identifying several novel miRNAs with putative oncogenic or tumor suppressor functions in T-ALL. Altogether, this study provides a comprehensive overview of miRNA expression in normal and malignant T-cells and sets the stage for functional evaluation of novel miRNAs in T-ALL disease biology.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that can be classified into different molecular genetic subtypes according to their mRNA gene expression profile. In this study, we applied RNA sequencing to investigate the full spectrum of miRNA expression in primary T-ALL patient samples, T-ALL leukemia cell lines and healthy donor thymocytes. Notably, this analysis revealed that genetic subtypes of human T-ALL also display unique miRNA expression signatures, which are largely conserved in human T-ALL cell lines with corresponding genetic background. Furthermore, small RNA-sequencing also unraveled the variety of isoforms that are expressed for each miRNA in T-ALL and showed that a significant number of miRNAs are actually represented by an alternative isomiR. Finally, comparison of CD34 and CD4 CD8 healthy donor thymocytes and T-ALL miRNA profiles allowed identifying several novel miRNAs with putative oncogenic or tumor suppressor functions in T-ALL. Altogether, this study provides a comprehensive overview of miRNA expression in normal and malignant T-cells and sets the stage for functional evaluation of novel miRNAs in T-ALL disease biology.
Acker, Aline Van; Gronke, Konrad; Biswas, Aindrila; Martens, Liesbet; Saeys, Yvan; Filtjens, Jessica; Taveirne, Sylvie; Ammel, Els Van; Kerre, Tessa; Matthys, Patrick; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Dunay, Ildiko Rita; Diefenbach, Andreas; Leclercq, Georges
A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties. Journal Article
In: Cell reports, vol. 19, pp. 1431–1443, 2017, ISSN: 2211-1247.
@article{VanAcker2017,
title = {A Murine Intestinal Intraepithelial NKp46-Negative Innate Lymphoid Cell Population Characterized by Group 1 Properties.},
author = {Aline Van Acker and Konrad Gronke and Aindrila Biswas and Liesbet Martens and Yvan Saeys and Jessica Filtjens and Sylvie Taveirne and Els Van Ammel and Tessa Kerre and Patrick Matthys and Tom Taghon and Bart Vandekerckhove and Jean Plum and Ildiko Rita Dunay and Andreas Diefenbach and Georges Leclercq},
doi = {10.1016/j.celrep.2017.04.068},
issn = {2211-1247},
year = {2017},
date = {2017-05-01},
journal = {Cell reports},
volume = {19},
pages = {1431--1443},
abstract = {The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα T lymphocytes, and CD49a liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46 CD8αα Ly49E cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
The Ly49E receptor is preferentially expressed on murine innate-like lymphocytes, such as epidermal Vγ3 T cells, intestinal intraepithelial CD8αα T lymphocytes, and CD49a liver natural killer (NK) cells. As the latter have recently been shown to be distinct from conventional NK cells and have innate lymphoid cell type 1 (ILC1) properties, we investigated Ly49E expression on intestinal ILC populations. Here, we show that Ly49E expression is very low on known ILC populations, but it can be used to define a previously unrecognized intraepithelial innate lymphoid population. This Ly49E-positive population is negative for NKp46 and CD8αα, expresses CD49a and CD103, and requires T-bet expression and IL-15 signaling for differentiation and/or survival. Transcriptome analysis reveals a group 1 ILC gene profile, different from NK cells, iCD8α cells, and intraepithelial ILC1. Importantly, NKp46 CD8αα Ly49E cells produce interferon (IFN)-γ, suggesting that this previously unrecognized population may contribute to Th1-mediated immunity.
Dolens, Anne-Catherine; Taghon, Tom
Human T cell development notched up a level. Journal Article
In: Nature methods, vol. 14, pp. 477–478, 2017, ISSN: 1548-7105.
@article{Dolens2017,
title = {Human T cell development notched up a level.},
author = {Anne-Catherine Dolens and Tom Taghon},
doi = {10.1038/nmeth.4277},
issn = {1548-7105},
year = {2017},
date = {2017-04-01},
journal = {Nature methods},
volume = {14},
pages = {477--478},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Verstichel, Greet; Vermijlen, David; Martens, Liesbet; Goetgeluk, Glenn; Brouwer, Margreet; Thiault, Nicolas; Caeneghem, Yasmine Van; Munter, Stijn De; Weening, Karin; Bonte, Sarah; Leclercq, Georges; Taghon, Tom; Kerre, Tessa; Saeys, Yvan; Dorpe, Jo Van; Cheroutre, Hilde; Vandekerckhove, Bart
The checkpoint for agonist selection precedes conventional selection in human thymus. Journal Article
In: Science immunology, vol. 2, 2017, ISSN: 2470-9468.
@article{Verstichel2017,
title = {The checkpoint for agonist selection precedes conventional selection in human thymus.},
author = {Greet Verstichel and David Vermijlen and Liesbet Martens and Glenn Goetgeluk and Margreet Brouwer and Nicolas Thiault and Yasmine Van Caeneghem and Stijn De Munter and Karin Weening and Sarah Bonte and Georges Leclercq and Tom Taghon and Tessa Kerre and Yvan Saeys and Jo Van Dorpe and Hilde Cheroutre and Bart Vandekerckhove},
doi = {10.1126/sciimmunol.aah4232},
issn = {2470-9468},
year = {2017},
date = {2017-02-01},
journal = {Science immunology},
volume = {2},
abstract = {The thymus plays a central role in self-tolerance, partly by eliminating precursors with a T cell receptor (TCR) that binds strongly to self-antigens. However, the generation of self-agonist-selected lineages also relies on strong TCR signaling. How thymocytes discriminate between these opposite outcomes remains elusive. Here, we identified a human agonist-selected PD-1 CD8αα subset of mature CD8αβ T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post-β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAV) and T cell receptor alpha joining (TRAJ) rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in the human thymus.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
The thymus plays a central role in self-tolerance, partly by eliminating precursors with a T cell receptor (TCR) that binds strongly to self-antigens. However, the generation of self-agonist-selected lineages also relies on strong TCR signaling. How thymocytes discriminate between these opposite outcomes remains elusive. Here, we identified a human agonist-selected PD-1 CD8αα subset of mature CD8αβ T cells that displays an effector phenotype associated with agonist selection. TCR stimulation of immature post-β-selection thymocyte blasts specifically gives rise to this innate subset and fixes early T cell receptor alpha variable (TRAV) and T cell receptor alpha joining (TRAJ) rearrangements in the TCR repertoire. These findings suggest that the checkpoint for agonist selection precedes conventional selection in the human thymus.
Wallaert, Annelynn; Durinck, Kaat; Taghon, Tom; Vlierberghe, Pieter Van; Speleman, Frank
T-ALL and thymocytes: a message of noncoding RNAs. Journal Article
In: Journal of hematology & oncology, vol. 10, pp. 66, 2017, ISSN: 1756-8722.
@article{Wallaert2017a,
title = {T-ALL and thymocytes: a message of noncoding RNAs.},
author = {Annelynn Wallaert and Kaat Durinck and Tom Taghon and Pieter Van Vlierberghe and Frank Speleman},
doi = {10.1186/s13045-017-0432-0},
issn = {1756-8722},
year = {2017},
date = {2017-01-01},
journal = {Journal of hematology & oncology},
volume = {10},
pages = {66},
abstract = {In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
In the last decade, the role for noncoding RNAs in disease was clearly established, starting with microRNAs and later expanded towards long noncoding RNAs. This was also the case for T cell acute lymphoblastic leukemia, which is a malignant blood disorder arising from oncogenic events during normal T cell development in the thymus. By studying the transcriptomic profile of protein-coding genes, several oncogenic events leading to T cell acute lymphoblastic leukemia (T-ALL) could be identified. In recent years, it became apparent that several of these oncogenes function via microRNAs and long noncoding RNAs. In this review, we give a detailed overview of the studies that describe the noncoding RNAome in T-ALL oncogenesis and normal T cell development.
Caeneghem, Yasmine Van; Munter, Stijn De; Tieppo, Paola; Goetgeluk, Glenn; Weening, Karin; Verstichel, Greet; Bonte, Sarah; Taghon, Tom; Leclercq, Georges; Kerre, Tessa; Debets, Reno; Vermijlen, David; Abken, Hinrich; Vandekerckhove, Bart
In: Oncoimmunology, vol. 6, pp. e1283460, 2017, ISSN: 2162-4011.
@article{VanCaeneghem2017,
title = {Antigen receptor-redirected T cells derived from hematopoietic precursor cells lack expression of the endogenous TCR/CD3 receptor and exhibit specific antitumor capacities.},
author = {Yasmine Van Caeneghem and Stijn De Munter and Paola Tieppo and Glenn Goetgeluk and Karin Weening and Greet Verstichel and Sarah Bonte and Tom Taghon and Georges Leclercq and Tessa Kerre and Reno Debets and David Vermijlen and Hinrich Abken and Bart Vandekerckhove},
doi = {10.1080/2162402X.2017.1283460},
issn = {2162-4011},
year = {2017},
date = {2017-01-01},
journal = {Oncoimmunology},
volume = {6},
pages = {e1283460},
abstract = {Recent clinical studies indicate that adoptive T-cell therapy and especially chimeric antigen receptor (CAR) T-cell therapy is a very potent and potentially curative treatment for B-lineage hematologic malignancies. Currently, autologous peripheral blood T cells are used for adoptive T-cell therapy. Adoptive T cells derived from healthy allogeneic donors may have several advantages; however, the expected occurrence of graft versus host disease (GvHD) as a consequence of the diverse allogeneic T-cell receptor (TCR) repertoire expressed by these cells compromises this approach. Here, we generated T cells from cord blood hematopoietic progenitor cells (HPCs) that were transduced to express an antigen receptor (AR): either a CAR or a TCR with or without built-in CD28 co-stimulatory domains. These AR-transgenic HPCs were culture-expanded on an OP9-DL1 feeder layer and subsequently differentiated to CD5 CD7 T-lineage precursors, to CD4 CD8 double positive cells and finally to mature AR T cells. The AR T cells were largely naive CD45RA CD62L T cells. These T cells had mostly germline TCRα and TCRβ loci and therefore lacked surface-expressed CD3/TCRαβ complexes. The CD3 AR-transgenic cells were mono-specific, functional T cells as they displayed specific cytotoxic activity. Cytokine production, including IL-2, was prominent in those cells bearing ARs with built-in CD28 domains. Data sustain the concept that cord blood HPC derived, generated allogeneic CD3 AR T cells can be used to more effectively eliminate malignant cells, while at the same time limiting the occurrence of GvHD.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Recent clinical studies indicate that adoptive T-cell therapy and especially chimeric antigen receptor (CAR) T-cell therapy is a very potent and potentially curative treatment for B-lineage hematologic malignancies. Currently, autologous peripheral blood T cells are used for adoptive T-cell therapy. Adoptive T cells derived from healthy allogeneic donors may have several advantages; however, the expected occurrence of graft versus host disease (GvHD) as a consequence of the diverse allogeneic T-cell receptor (TCR) repertoire expressed by these cells compromises this approach. Here, we generated T cells from cord blood hematopoietic progenitor cells (HPCs) that were transduced to express an antigen receptor (AR): either a CAR or a TCR with or without built-in CD28 co-stimulatory domains. These AR-transgenic HPCs were culture-expanded on an OP9-DL1 feeder layer and subsequently differentiated to CD5 CD7 T-lineage precursors, to CD4 CD8 double positive cells and finally to mature AR T cells. The AR T cells were largely naive CD45RA CD62L T cells. These T cells had mostly germline TCRα and TCRβ loci and therefore lacked surface-expressed CD3/TCRαβ complexes. The CD3 AR-transgenic cells were mono-specific, functional T cells as they displayed specific cytotoxic activity. Cytokine production, including IL-2, was prominent in those cells bearing ARs with built-in CD28 domains. Data sustain the concept that cord blood HPC derived, generated allogeneic CD3 AR T cells can be used to more effectively eliminate malignant cells, while at the same time limiting the occurrence of GvHD.