Publications
2021
Moirangthem, Ranjita Devi; Ma, Kuiying; Lizot, Sabrina; Cordesse, Anne; Olivré, Juliette; de Chappedelaine, Corinne; Joshi, Akshay; Cieslak, Agata; Tchen, John; Cagnard, Nicolas; Asnafi, Vahid; Rausell, Antonio; Simons, Laura; Zuber, Julien; Taghon, Tom; Staal, Frank J T; Pflumio, Françoise; Six, Emmanuelle; Cavazzana, Marina; Lagresle-Peyrou, Chantal; Soheili, Tayebeh; André, Isabelle
In: Cellular & molecular immunology, vol. 18, pp. 1662–1676, 2021, ISSN: 2042-0226.
@article{Moirangthem2021,
title = {A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors.},
author = {Ranjita Devi Moirangthem and Kuiying Ma and Sabrina Lizot and Anne Cordesse and Juliette Olivré and Corinne de Chappedelaine and Akshay Joshi and Agata Cieslak and John Tchen and Nicolas Cagnard and Vahid Asnafi and Antonio Rausell and Laura Simons and Julien Zuber and Tom Taghon and Frank J T Staal and Françoise Pflumio and Emmanuelle Six and Marina Cavazzana and Chantal Lagresle-Peyrou and Tayebeh Soheili and Isabelle André},
doi = {10.1038/s41423-021-00706-8},
issn = {2042-0226},
year = {2021},
date = {2021-07-01},
journal = {Cellular & molecular immunology},
volume = {18},
pages = {1662--1676},
abstract = {Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Kiekens, Laura; Loocke, Wouter Van; Taveirne, Sylvie; Wahlen, Sigrid; Persyn, Eva; Ammel, Els Van; Vos, Zenzi De; Matthys, Patrick; Nieuwerburgh, Filip Van; Taghon, Tom; Vlierberghe, Pieter Van; Vandekerckhove, Bart; Leclercq, Georges
T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells. Journal Article
In: Frontiers in immunology, vol. 12, pp. 732511, 2021, ISSN: 1664-3224.
@article{Kiekens2021,
title = {T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells.},
author = {Laura Kiekens and Wouter Van Loocke and Sylvie Taveirne and Sigrid Wahlen and Eva Persyn and Els Van Ammel and Zenzi De Vos and Patrick Matthys and Filip Van Nieuwerburgh and Tom Taghon and Pieter Van Vlierberghe and Bart Vandekerckhove and Georges Leclercq},
doi = {10.3389/fimmu.2021.732511},
issn = {1664-3224},
year = {2021},
date = {2021-01-01},
journal = {Frontiers in immunology},
volume = {12},
pages = {732511},
abstract = {T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Lorenzi, Lucia; Chiu, Hua-Sheng; Cobos, Francisco Avila; Gross, Stephen; Volders, Pieter-Jan; Cannoodt, Robrecht; Nuytens, Justine; Vanderheyden, Katrien; Anckaert, Jasper; Lefever, Steve; Tay, Aidan P; de Bony, Eric J; Trypsteen, Wim; Gysens, Fien; Vromman, Marieke; Goovaerts, Tine; Hansen, Thomas Birkballe; Kuersten, Scott; Nijs, Nele; Taghon, Tom; Vermaelen, Karim; Bracke, Ken R; Saeys, Yvan; Meyer, Tim De; Deshpande, Nandan P; Anande, Govardhan; Chen, Ting-Wen; Wilkins, Marc R; Unnikrishnan, Ashwin; Preter, Katleen De; Kjems, Jørgen; Koster, Jan; Schroth, Gary P; Vandesompele, Jo; Sumazin, Pavel; Mestdagh, Pieter
Publisher Correction: The RNA Atlas expands the catalog of human non-coding RNAs. Journal Article
In: Nature biotechnology, vol. 39, pp. 1467, 2021, ISSN: 1546-1696.
@article{Lorenzi2021,
title = {Publisher Correction: The RNA Atlas expands the catalog of human non-coding RNAs.},
author = {Lucia Lorenzi and Hua-Sheng Chiu and Francisco Avila Cobos and Stephen Gross and Pieter-Jan Volders and Robrecht Cannoodt and Justine Nuytens and Katrien Vanderheyden and Jasper Anckaert and Steve Lefever and Aidan P Tay and Eric J de Bony and Wim Trypsteen and Fien Gysens and Marieke Vromman and Tine Goovaerts and Thomas Birkballe Hansen and Scott Kuersten and Nele Nijs and Tom Taghon and Karim Vermaelen and Ken R Bracke and Yvan Saeys and Tim De Meyer and Nandan P Deshpande and Govardhan Anande and Ting-Wen Chen and Marc R Wilkins and Ashwin Unnikrishnan and Katleen De Preter and Jørgen Kjems and Jan Koster and Gary P Schroth and Jo Vandesompele and Pavel Sumazin and Pieter Mestdagh},
doi = {10.1038/s41587-021-00996-3},
issn = {1546-1696},
year = {2021},
date = {2021-01-01},
journal = {Nature biotechnology},
volume = {39},
pages = {1467},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Ingels, Joline; Smet, Saskia De; Heyns, Kelly; Lootens, Nele; Segaert, Jonas; Taghon, Tom; Leclercq, Georges; Vermaelen, Karim; Willems, Evelyne; Baudoux, Etienne; Kerre, Tessa; Baron, Frédéric; Vandekerckhove, Bart
In: Acta clinica Belgica, vol. 76, pp. 482–486, 2021, ISSN: 2295-3337.
@article{Ingels2021,
title = {Treatment of a patient with severe cytomegalovirus (CMV) infection after haploidentical stem cell transplantation with donor derived CMV specific T cells.},
author = {Joline Ingels and Saskia De Smet and Kelly Heyns and Nele Lootens and Jonas Segaert and Tom Taghon and Georges Leclercq and Karim Vermaelen and Evelyne Willems and Etienne Baudoux and Tessa Kerre and Frédéric Baron and Bart Vandekerckhove},
doi = {10.1080/17843286.2020.1752446},
issn = {2295-3337},
year = {2021},
date = {2021-01-01},
journal = {Acta clinica Belgica},
volume = {76},
pages = {482--486},
abstract = {Cytomegalovirus (CMV) infection is one of the most common complications in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. The classic antiviral treatments have shown clinical efficacy but are often associated with drug resistance. Reconstitution of CMV-specific cellular immunity is essential in controlling CMV infection; therefore, adoptive transfer of CMV-specific T cells is a promising treatment option. We treated a patient with a multidrug resistant CMV infection after haploidentical HSCT with CMV-specific T cells. The T cells were derived from the HSCT donor who was CMV seropositive. We generated the T cells by a short-term Good Manufacturing Practice (GMP) grade protocol in which a leukapheresis product of the HSCT donor was stimulated with the immunodominant antigen pp65 and interferon-γ secreting cells were isolated. A total of 5 × 10 T cells were administered to the patient within 30 hours after leukapheresis. The patient was closely monitored for reconstitution of antiviral T cell immunity and viral replication after adoptive T cell transfer. We observed an in vivo expansion of both CD4 and CD8 CMV-specific T cells associated with a significant decrease in viral burden and clinical improvement. This case report further supports the feasibility and effectiveness of adoptive donor T cell transfer for the treatment of drug resistant CMV infections after allo-HSCT.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Ferrua, Francesca; Bortolomai, Ileana; Fontana, Elena; Silvestre, Dario Di; Rigoni, Rosita; Marcovecchio, Genni Enza; Draghici, Elena; Brambilla, Francesca; Castiello, Maria Carmina; Delfanti, Gloria; Moshous, Despina; Picard, Capucine; Taghon, Tom; Bordon, Victoria; Schulz, Ansgar S; Schuetz, Catharina; Giliani, Silvia; Soresina, Annarosa; Gennery, Andrew R; Signa, Sara; Saldaña, Blachy J Dávila; Delmonte, Ottavia M; Notarangelo, Luigi D; Roifman, Chaim M; Poliani, Pietro Luigi; Uva, Paolo; Mauri, Pier Luigi; Villa, Anna; Bosticardo, Marita
Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency. Journal Article
In: Frontiers in immunology, vol. 12, pp. 669943, 2021, ISSN: 1664-3224.
@article{Ferrua2021,
title = {Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency.},
author = {Francesca Ferrua and Ileana Bortolomai and Elena Fontana and Dario Di Silvestre and Rosita Rigoni and Genni Enza Marcovecchio and Elena Draghici and Francesca Brambilla and Maria Carmina Castiello and Gloria Delfanti and Despina Moshous and Capucine Picard and Tom Taghon and Victoria Bordon and Ansgar S Schulz and Catharina Schuetz and Silvia Giliani and Annarosa Soresina and Andrew R Gennery and Sara Signa and Blachy J Dávila Saldaña and Ottavia M Delmonte and Luigi D Notarangelo and Chaim M Roifman and Pietro Luigi Poliani and Paolo Uva and Pier Luigi Mauri and Anna Villa and Marita Bosticardo},
doi = {10.3389/fimmu.2021.669943},
issn = {1664-3224},
year = {2021},
date = {2021-01-01},
journal = {Frontiers in immunology},
volume = {12},
pages = {669943},
abstract = {Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Decker, Matthias De; Lavaert, Marieke; Roels, Juliette; Tilleman, Laurentijn; Vandekerckhove, Bart; Leclercq, Georges; Nieuwerburgh, Filip Van; Vlierberghe, Pieter Van; Taghon, Tom
HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development. Journal Article
In: Haematologica, vol. 106, pp. 130–141, 2021, ISSN: 1592-8721.
@article{DeDecker2021,
title = {HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development.},
author = {Matthias De Decker and Marieke Lavaert and Juliette Roels and Laurentijn Tilleman and Bart Vandekerckhove and Georges Leclercq and Filip Van Nieuwerburgh and Pieter Van Vlierberghe and Tom Taghon},
doi = {10.3324/haematol.2019.226126},
issn = {1592-8721},
year = {2021},
date = {2021-01-01},
journal = {Haematologica},
volume = {106},
pages = {130--141},
abstract = {In both mouse and human, Notch1 activation is the main initial driver to induce T-cell development in hematopoietic progenitor cells. The initiation of this developmental process coincides with Notch1-dependent repression of differentiation towards other hematopoietic lineages. Although well described in mice, the role of the individual Notch1 target genes during these hematopoietic developmental choices is still unclear in human, particularly for HES4 since no orthologous gene is present in the mouse. Here, we investigated the functional capacity of the Notch1 target genes HES1 and HES4 to modulate human Notch1-dependent hematopoietic lineage decisions and their requirement during early T-cell development. We show that both genes are upregulated in a Notch-dependent manner during early T-cell development and that HES1 acts as a repressor of differentiation by maintaining a quiescent stem cell signature in CD34+ hematopoietic progenitor cells. While HES4 can also inhibit natural killer and myeloid cell development like HES1, it acts differently on the T- versus B-cell lineage choice. Surprisingly, HES4 is not capable of repressing B-cell development, the most sensitive hematopoietic lineage with respect to Notch-mediated repression. In contrast to HES1, HES4 promotes initiation of early T-cell development, but ectopic expression of HES4, or HES1 and HES4 combined, is not sufficient to induce T-lineage differentiation. Importantly, knockdown of HES1 or HES4 significantly reduces human T-cell development. Overall, we show that the Notch1 target genes HES1 and HES4 have non-redundant roles during early human T-cell development which may relate to differences in mediating Notch-dependent human hematopoietic lineage decisions.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Tottone, Luca; Lancho, Olga; Loh, Jui-Wan; Singh, Amartya; Kimura, Shunsuke; Roels, Juliette; Kuchmiy, Anna; Strubbe, Steven; Lawlor, Matthew A; da Silva-Diz, Victoria; Luo, Shirley; Gachet, Stéphanie; García-Prieto, Carlos A; Hagelaar, Rico; Esteller, Manel; Meijerink, Jules P P; Soulier, Jean; Taghon, Tom; Vlierberghe, Pieter Van; Mullighan, Charles G; Khiabanian, Hossein; Rocha, Pedro P; Herranz, Daniel
A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia. Journal Article
In: Blood cancer discovery, vol. 2, pp. 92–109, 2021, ISSN: 2643-3249.
@article{Tottone2021,
title = {A Tumor Suppressor Enhancer of PTEN in T-cell development and leukemia.},
author = {Luca Tottone and Olga Lancho and Jui-Wan Loh and Amartya Singh and Shunsuke Kimura and Juliette Roels and Anna Kuchmiy and Steven Strubbe and Matthew A Lawlor and Victoria da Silva-Diz and Shirley Luo and Stéphanie Gachet and Carlos A García-Prieto and Rico Hagelaar and Manel Esteller and Jules P P Meijerink and Jean Soulier and Tom Taghon and Pieter Van Vlierberghe and Charles G Mullighan and Hossein Khiabanian and Pedro P Rocha and Daniel Herranz},
doi = {10.1158/2643-3230.BCD-20-0201},
issn = {2643-3249},
year = {2021},
date = {2021-01-01},
journal = {Blood cancer discovery},
volume = {2},
pages = {92--109},
abstract = {Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia (T-ALL). Here, we identify a highly conserved distal enhancer (PE) that interacts with the promoter in multiple hematopoietic populations, including T-cells, and acts as a hub of relevant transcription factors in T-ALL. Consistently, loss of PE leads to reduced levels in T-ALL cells. Moreover, PE-null mice show reduced levels in thymocytes and accelerated development of NOTCH1-induced T-ALL. Furthermore, secondary loss of PE in established leukemias leads to accelerated progression and a gene expression signature driven by loss. Finally, we uncovered recurrent deletions encompassing PE in T-ALL, which are associated with decreased levels. Altogether, our results identify PE as the first long-range tumor suppressor enhancer directly implicated in cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Strubbe, Steven; Bruyne, Marieke De; Pannicke, Ulrich; Beyls, Elien; Vandekerckhove, Bart; Leclercq, Georges; Baere, Elfride De; Bordon, Victoria; Vral, Anne; Schwarz, Klaus; Haerynck, Filomeen; Taghon, Tom
In: Frontiers in immunology, vol. 12, pp. 674226, 2021, ISSN: 1664-3224.
@article{Strubbe2021a,
title = {A Novel Non-Coding Variant in DCLRE1C Results in Deregulated Splicing and Induces SCID Through the Generation of a Truncated ARTEMIS Protein That Fails to Support V(D)J Recombination and DNA Damage Repair.},
author = {Steven Strubbe and Marieke De Bruyne and Ulrich Pannicke and Elien Beyls and Bart Vandekerckhove and Georges Leclercq and Elfride De Baere and Victoria Bordon and Anne Vral and Klaus Schwarz and Filomeen Haerynck and Tom Taghon},
doi = {10.3389/fimmu.2021.674226},
issn = {1664-3224},
year = {2021},
date = {2021-01-01},
journal = {Frontiers in immunology},
volume = {12},
pages = {674226},
abstract = {Severe Combined Immune Deficiency (SCID) is a primary deficiency of the immune system in which opportunistic and recurring infections are often fatal during neonatal or infant life. SCID is caused by an increasing number of genetic defects that induce an abrogation of T lymphocyte development or function in which B and NK cells might be affected as well. Because of the increased availability and usage of next-generation sequencing (NGS), many novel variants in SCID genes are being identified and cause a heterogeneous disease spectrum. However, the molecular and functional implications of these new variants, of which some are non-coding, are often not characterized in detail. Using targeted NGS, we identified a novel homozygous c.465-1G>C splice acceptor site variant in the gene in a T B NK SCID patient and fully characterized the molecular and functional impact. By performing a minigene splicing reporter assay, we revealed deregulated splicing of the transcript since a cryptic splice acceptor in exon 7 was employed. This induced a frameshift and the generation of a p.Arg155Serfs*15 premature termination codon (PTC) within all splice variants, resulting in the absence of full-length ARTEMIS protein. Consistently, a V(D)J recombination assay and a G0 micronucleus assay demonstrated the inability of the predicted mutant ARTEMIS protein to perform V(D)J recombination and DNA damage repair, respectively. Together, these experiments molecularly and functionally clarify how a newly identified c.465-1G>C variant in the gene is responsible for inducing SCID. In a clinical context, this demonstrates how the experimental validation of new gene variants, that are identified by NGS, can facilitate the diagnosis of SCID which can be vital for implementing appropriate therapies.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Bonte, Sarah; de Munter, Stijn; Billiet, Lore; Goetgeluk, Glenn; Ingels, Joline; Jansen, Hanne; Pille, Melissa; de Cock, Laurenz; Weening, Karin; Taghon, Tom; Leclercq, Georges; Vandekerckhove, Bart; Kerre, Tessa
In: Oncoimmunology, vol. 10, pp. 1954800, 2021, ISSN: 2162-402X.
@article{Bonte2021,
title = {In vitro OP9-DL1 co-culture and subsequent maturation in the presence of IL-21 generates tumor antigen-specific T cells with a favorable less-differentiated phenotype and enhanced functionality.},
author = {Sarah Bonte and Stijn de Munter and Lore Billiet and Glenn Goetgeluk and Joline Ingels and Hanne Jansen and Melissa Pille and Laurenz de Cock and Karin Weening and Tom Taghon and Georges Leclercq and Bart Vandekerckhove and Tessa Kerre},
doi = {10.1080/2162402X.2021.1954800},
issn = {2162-402X},
year = {2021},
date = {2021-01-01},
journal = {Oncoimmunology},
volume = {10},
pages = {1954800},
abstract = {T cell receptor (TCR)-redirected T cells target intracellular antigens such as Wilms' tumor 1 (WT1), a tumor-associated antigen overexpressed in several malignancies, including acute myeloid leukemia (AML). For both chimeric antigen receptor (CAR)- and TCR-redirected T cells, several clinical studies indicate that T cell subsets with a less-differentiated phenotype (e.g. stem cell memory T cells, T ) survive longer and mediate superior anti-tumor effects as opposed to more terminally differentiated T cells. Cytokines added during and culture of T cells play an important role in driving the phenotype of T cells for adoptive transfer. Using the OP9-DL1 co-culture system, we have shown previously that we are able to generate , starting from clinically relevant stem cell sources, T cells with a single tumor antigen (TA)-specific TCR. This method circumvents possible TCR chain mispairing and unwanted toxicities that might occur when introducing a TA-specific TCR in peripheral blood lymphocytes. We now show that we are able to optimize our culture protocol, by adding IL-21 during maturation, resulting in generation of TA-specific T cells with a less-differentiated phenotype and enhanced anti-tumor effects. We believe the favorable T -like phenotype of these generated T cells preludes superior persistence and anti-tumor efficacy. Therefore, these TA-specific T cells could be of use as a valuable new form of patient-tailored T cell immunotherapy for malignancies for which finding a suitable CAR-T target antigen is challenging, such as AML.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Buratin, Alessia; Paganin, Maddalena; Gaffo, Enrico; Molin, Anna Dal; Roels, Juliette; Germano, Giuseppe; Siddi, Maria Teresa; Serafin, Valentina; Decker, Matthias De; Gachet, Stéphanie; Durinck, Kaat; Speleman, Frank; Taghon, Tom; Kronnie, Geertruij Te; Vlierberghe, Pieter Van; Bortoluzzi, Stefania
Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes. Journal Article
In: Blood advances, vol. 4, pp. 5902–5914, 2020, ISSN: 2473-9537.
@article{Buratin2020,
title = {Large-scale circular RNA deregulation in T-ALL: unlocking unique ectopic expression of molecular subtypes.},
author = {Alessia Buratin and Maddalena Paganin and Enrico Gaffo and Anna Dal Molin and Juliette Roels and Giuseppe Germano and Maria Teresa Siddi and Valentina Serafin and Matthias De Decker and Stéphanie Gachet and Kaat Durinck and Frank Speleman and Tom Taghon and Geertruij Te Kronnie and Pieter Van Vlierberghe and Stefania Bortoluzzi},
doi = {10.1182/bloodadvances.2020002337},
issn = {2473-9537},
year = {2020},
date = {2020-12-01},
journal = {Blood advances},
volume = {4},
pages = {5902--5914},
abstract = {Circular RNAs (circRNAs) are stable RNA molecules that can drive cancer through interactions with microRNAs and proteins and by the expression of circRNA encoded peptides. The aim of the study was to define the circRNA landscape and potential impact in T-cell acute lymphoblastic leukemia (T-ALL). Analysis by CirComPara of RNA-sequencing data from 25 T-ALL patients, immature, HOXA overexpressing, TLX1, TLX3, TAL1, or LMO2 rearranged, and from thymocyte populations of human healthy donors disclosed 68 554 circRNAs. Study of the top 3447 highly expressed circRNAs identified 944 circRNAs with significant differential expression between malignant T cells and normal counterparts, with most circRNAs displaying increased expression in T-ALL. Next, we defined subtype-specific circRNA signatures in molecular genetic subgroups of human T-ALL. In particular, circZNF609, circPSEN1, circKPNA5, and circCEP70 were upregulated in immature, circTASP1, circZBTB44, and circBACH1 in TLX3, circHACD1, and circSTAM in HOXA, circCAMSAP1 in TLX1, and circCASC15 in TAL-LMO. Backsplice sequences of 14 circRNAs ectopically expressed in T-ALL were confirmed, and overexpression of circRNAs in T-ALL with specific oncogenic lesions was substantiated by quantification in a panel of 13 human cell lines. An oncogenic role of circZNF609 in T-ALL was indicated by decreased cell viability upon silencing in vitro. Furthermore, functional predictions identified circRNA-microRNA gene axes informing modes of circRNA impact in molecular subtypes of human T-ALL.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Roels, Juliette; Thénoz, Morgan; Szarzyńska, Bronisława; Landfors, Mattias; Coninck, Stien De; Demoen, Lisa; Provez, Lien; Kuchmiy, Anna; Strubbe, Steven; Reunes, Lindy; Pieters, Tim; Matthijssens, Filip; Loocke, Wouter Van; Erarslan-Uysal, Büşra; Richter-Pechańska, Paulina; Declerck, Ken; Lammens, Tim; Moerloose, Barbara De; Deforce, Dieter; Nieuwerburgh, Filip Van; Cheung, Laurence C; Kotecha, Rishi S; Mansour, Marc R; Ghesquière, Bart; Camp, Guy Van; Berghe, Wim Vanden; Kowalczyk, Jerzy R; Szczepański, Tomasz; Davé, Utpal P; Kulozik, Andreas E; Goossens, Steven; Curtis, David J; Taghon, Tom; Dawidowska, Małgorzata; Degerman, Sofie; Vlierberghe, Pieter Van
Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia. Journal Article
In: Blood cancer discovery, vol. 1, pp. 274–289, 2020, ISSN: 2643-3249.
@article{Roels2020,
title = {Aging of preleukemic thymocytes drives CpG island hypermethylation in T-cell acute lymphoblastic leukemia.},
author = {Juliette Roels and Morgan Thénoz and Bronisława Szarzyńska and Mattias Landfors and Stien De Coninck and Lisa Demoen and Lien Provez and Anna Kuchmiy and Steven Strubbe and Lindy Reunes and Tim Pieters and Filip Matthijssens and Wouter Van Loocke and Büşra Erarslan-Uysal and Paulina Richter-Pechańska and Ken Declerck and Tim Lammens and Barbara De Moerloose and Dieter Deforce and Filip Van Nieuwerburgh and Laurence C Cheung and Rishi S Kotecha and Marc R Mansour and Bart Ghesquière and Guy Van Camp and Wim Vanden Berghe and Jerzy R Kowalczyk and Tomasz Szczepański and Utpal P Davé and Andreas E Kulozik and Steven Goossens and David J Curtis and Tom Taghon and Małgorzata Dawidowska and Sofie Degerman and Pieter Van Vlierberghe},
doi = {10.1158/2643-3230.BCD-20-0059},
issn = {2643-3249},
year = {2020},
date = {2020-11-01},
journal = {Blood cancer discovery},
volume = {1},
pages = {274--289},
abstract = {Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of T-ALL and is established already in pre-leukemic, self-renewing thymocytes that precede T-ALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in T-ALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human T-ALL.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Billiet, Lore; Goetgeluk, Glenn; Bonte, Sarah; Munter, Stijn De; Cock, Laurenz De; Pille, Melissa; Ingels, Joline; Jansen, Hanne; Weening, Karin; Nieuwerburgh, Filip Van; Kerre, Tessa; Taghon, Tom; Leclercq, Georges; Vandekerckhove, Bart
In: International journal of molecular sciences, vol. 21, 2020, ISSN: 1422-0067.
@article{Billiet2020,
title = {Human Thymic CD10+ PD-1+ Intraepithelial Lymphocyte Precursors Acquire Interleukin-15 Responsiveness at the CD1a– CD95+ CD28– CCR7– Developmental Stage},
author = {Lore Billiet and Glenn Goetgeluk and Sarah Bonte and Stijn De Munter and Laurenz De Cock and Melissa Pille and Joline Ingels and Hanne Jansen and Karin Weening and Filip Van Nieuwerburgh and Tessa Kerre and Tom Taghon and Georges Leclercq and Bart Vandekerckhove},
doi = {10.3390/ijms21228785},
issn = {1422-0067},
year = {2020},
date = {2020-11-01},
journal = {International journal of molecular sciences},
volume = {21},
abstract = {Human thymic CD8αα CD10 PD-1 αβ T cells selected through early agonist selection have been proposed as the putative thymic precursors of the human CD8αα intestinal intraepithelial lymphocytes (IELs). However, the progeny of these thymic precursor cells in human blood or tissues has not yet been characterized. Here, we studied the phenotypical and transcriptional differentiation of the thymic IEL precursor (IELp) lineage upon in vitro exposure to cytokines prominent in the peripheral tissues such as interleukin-15 (IL-15) and the inflammatory cytokines interleukin-12 (IL-12) and interleukin-18 (IL-18). We showed that only the CD1a fraction of the CD10 PD-1 IELp population was able to proliferate with IL-15, suggesting that this subset had acquired functionality. These cells downregulated PD-1 expression and completely lost CD10 expression, whereas other surface markers such as CD95 and CXCR3 remained highly expressed. RNA-seq analysis of the IL-15-cultured cells clearly showed induction of innate-like and effector genes. Induction of the cytotoxic machinery by the CD10 PD-1 population was acquired in the presence of IL-15 and was further augmented by inflammatory cytokines. Our data suggest that only the CD1a CD10 PD-1 population exits the thymus and survives in the periphery. Furthermore, PD-1 and CD10 expression is not an intrinsic property of this lineage, but rather characterizes a transient stage in differentiation. CD95 and CXCR3 expression combined with the absence of CD28, CCR7, and CD6 expression might be more powerful markers to define this lineage in the periphery.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Taveirne, Sylvie; Wahlen, Sigrid; Loocke, Wouter Van; Kiekens, Laura; Persyn, Eva; Ammel, Els Van; Mulder, Katrien De; Roels, Juliette; Tilleman, Laurentijn; Aumercier, Marc; Matthys, Patrick; Nieuwerburgh, Filip Van; Kerre, Tessa C C; Taghon, Tom; Vlierberghe, Pieter Van; Vandekerckhove, Bart; Leclercq, Georges
The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation. Journal Article
In: Blood, vol. 136, pp. 288–298, 2020, ISSN: 1528-0020.
@article{Taveirne2020,
title = {The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation.},
author = {Sylvie Taveirne and Sigrid Wahlen and Wouter Van Loocke and Laura Kiekens and Eva Persyn and Els Van Ammel and Katrien De Mulder and Juliette Roels and Laurentijn Tilleman and Marc Aumercier and Patrick Matthys and Filip Van Nieuwerburgh and Tessa C C Kerre and Tom Taghon and Pieter Van Vlierberghe and Bart Vandekerckhove and Georges Leclercq},
doi = {10.1182/blood.2020005204},
issn = {1528-0020},
year = {2020},
date = {2020-07-01},
journal = {Blood},
volume = {136},
pages = {288--298},
abstract = {Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and they regulate other immune cells by cytokine secretion. Although murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells and by expressing the dominant-negative ETS1 p27 isoform in cord blood hematopoietic progenitor cells, we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation (ie, E4BP4, TXNIP, TBET, GATA3, HOBIT, BLIMP1). In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Smedt, Renate De; Morscio, Julie; Reunes, Lindy; Roels, Juliette; Bardelli, Valentina; Lintermans, Beatrice; Loocke, Wouter Van; Almeida, Afonso; Cheung, Laurence C; Kotecha, Rishi S; Mansour, Marc R; Uyttebroeck, Anne; Vandenberghe, Peter; Starza, Roberta La; Mecucci, Cristina; Lammens, Tim; Roy, Nadine Van; Moerloose, Barbara De; Barata, João T; Taghon, Tom; Goossens, Steven; Vlierberghe, Pieter Van
Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma. Journal Article
In: Blood, vol. 135, pp. 1685–1695, 2020, ISSN: 1528-0020.
@article{DeSmedt2020,
title = {Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma.},
author = {Renate De Smedt and Julie Morscio and Lindy Reunes and Juliette Roels and Valentina Bardelli and Beatrice Lintermans and Wouter Van Loocke and Afonso Almeida and Laurence C Cheung and Rishi S Kotecha and Marc R Mansour and Anne Uyttebroeck and Peter Vandenberghe and Roberta La Starza and Cristina Mecucci and Tim Lammens and Nadine Van Roy and Barbara De Moerloose and João T Barata and Tom Taghon and Steven Goossens and Pieter Van Vlierberghe},
doi = {10.1182/blood.2019003880},
issn = {1528-0020},
year = {2020},
date = {2020-05-01},
journal = {Blood},
volume = {135},
pages = {1685--1695},
abstract = {T-cell acute lymphoblastic leukemia (T-ALL) and T-cell acute lymphoblastic lymphoma (T-LBL) are aggressive hematological malignancies that are currently treated with high-dose chemotherapy. Over the last several years, the search toward novel and less-toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell-intrinsic properties of the tumor cell. However, non-cell-autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous interleukin 7 (IL7) can increase the expression of the oncogenic kinase proviral integration site for Moloney-murine leukemia 1 (PIM1) in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared with bulk nontreated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL patient-derived xenograft (PDX) cells, ultimately resulting in non-cell-autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7-responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Dolens, Anne-Catherine; Durinck, Kaat; Lavaert, Marieke; der Meulen, Joni Van; Velghe, Imke; Medts, Jelle De; Weening, Karin; Roels, Juliette; Mulder, Katrien De; Volders, Pieter-Jan; Preter, Katleen De; Kerre, Tessa; Vandekerckhove, Bart; Leclercq, Georges; Vandesompele, Jo; Mestdagh, Pieter; Vlierberghe, Pieter Van; Speleman, Frank; Taghon, Tom
Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development. Journal Article
In: EMBO reports, vol. 21, pp. e49006, 2020, ISSN: 1469-3178.
@article{Dolens2020,
title = {Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development.},
author = {Anne-Catherine Dolens and Kaat Durinck and Marieke Lavaert and Joni Van der Meulen and Imke Velghe and Jelle De Medts and Karin Weening and Juliette Roels and Katrien De Mulder and Pieter-Jan Volders and Katleen De Preter and Tessa Kerre and Bart Vandekerckhove and Georges Leclercq and Jo Vandesompele and Pieter Mestdagh and Pieter Van Vlierberghe and Frank Speleman and Tom Taghon},
doi = {10.15252/embr.201949006},
issn = {1469-3178},
year = {2020},
date = {2020-05-01},
journal = {EMBO reports},
volume = {21},
pages = {e49006},
abstract = {γδ and αβ T cells have unique roles in immunity and both originate in the thymus from T-lineage committed precursors through distinct but unclear mechanisms. Here, we show that Notch1 activation is more stringently required for human γδ development compared to αβ-lineage differentiation and performed paired mRNA and miRNA profiling across 11 discrete developmental stages of human T cell development in an effort to identify the potential Notch1 downstream mechanism. Our data suggest that the miR-17-92 cluster is a Notch1 target in immature thymocytes and that miR-17 can restrict BCL11B expression in these Notch-dependent T cell precursors. We show that enforced miR-17 expression promotes human γδ T cell development and, consistently, that BCL11B is absolutely required for αβ but less for γδ T cell development. This study suggests that human γδ T cell development is mediated by a stage-specific Notch-driven negative feedback loop through which miR-17 temporally restricts BCL11B expression and provides functional insights into the developmental role of the disease-associated genes BCL11B and the miR-17-92 cluster in a human context.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Park, Jong-Eun; Botting, Rachel A; Conde, Cecilia Domínguez; Popescu, Dorin-Mirel; Lavaert, Marieke; Kunz, Daniel J; Goh, Issac; Stephenson, Emily; Ragazzini, Roberta; Tuck, Elizabeth; Wilbrey-Clark, Anna; Roberts, Kenny; Kedlian, Veronika R; Ferdinand, John R; He, Xiaoling; Webb, Simone; Maunder, Daniel; Vandamme, Niels; Mahbubani, Krishnaa T; Polanski, Krzysztof; Mamanova, Lira; Bolt, Liam; Crossland, David; de Rita, Fabrizio; Fuller, Andrew; Filby, Andrew; Reynolds, Gary; Dixon, David; Saeb-Parsy, Kourosh; Lisgo, Steven; Henderson, Deborah; Vento-Tormo, Roser; Bayraktar, Omer A; Barker, Roger A; Meyer, Kerstin B; Saeys, Yvan; Bonfanti, Paola; Behjati, Sam; Clatworthy, Menna R; Taghon, Tom; Haniffa, Muzlifah; Teichmann, Sarah A
A cell atlas of human thymic development defines T cell repertoire formation. Journal Article
In: Science (New York, N.Y.), vol. 367, 2020, ISSN: 1095-9203.
@article{Park2020,
title = {A cell atlas of human thymic development defines T cell repertoire formation.},
author = {Jong-Eun Park and Rachel A Botting and Cecilia Domínguez Conde and Dorin-Mirel Popescu and Marieke Lavaert and Daniel J Kunz and Issac Goh and Emily Stephenson and Roberta Ragazzini and Elizabeth Tuck and Anna Wilbrey-Clark and Kenny Roberts and Veronika R Kedlian and John R Ferdinand and Xiaoling He and Simone Webb and Daniel Maunder and Niels Vandamme and Krishnaa T Mahbubani and Krzysztof Polanski and Lira Mamanova and Liam Bolt and David Crossland and Fabrizio de Rita and Andrew Fuller and Andrew Filby and Gary Reynolds and David Dixon and Kourosh Saeb-Parsy and Steven Lisgo and Deborah Henderson and Roser Vento-Tormo and Omer A Bayraktar and Roger A Barker and Kerstin B Meyer and Yvan Saeys and Paola Bonfanti and Sam Behjati and Menna R Clatworthy and Tom Taghon and Muzlifah Haniffa and Sarah A Teichmann},
doi = {10.1126/science.aay3224},
issn = {1095-9203},
year = {2020},
date = {2020-02-01},
journal = {Science (New York, N.Y.)},
volume = {367},
abstract = {The thymus provides a nurturing environment for the differentiation and selection of T cells, a process orchestrated by their interaction with multiple thymic cell types. We used single-cell RNA sequencing to create a cell census of the human thymus across the life span and to reconstruct T cell differentiation trajectories and T cell receptor (TCR) recombination kinetics. Using this approach, we identified and located in situ CD8αα T cell populations, thymic fibroblast subtypes, and activated dendritic cell states. In addition, we reveal a bias in TCR recombination and selection, which is attributed to genomic position and the kinetics of lineage commitment. Taken together, our data provide a comprehensive atlas of the human thymus across the life span with new insights into human T cell development.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
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}
}
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}
}
Zhou, Yalu; Han, Cuijuan; Wang, Eric; Lorch, Adam H; Serafin, Valentina; Cho, Byoung-Kyu; Diaz, Blanca T Gutierrez; Calvo, Julien; Fang, Celestia; Khodadadi-Jamayran, Alireza; Tabaglio, Tommaso; Marier, Christian; Kuchmiy, Anna; Sun, Limin; Yacu, George; Filip, Szymon K; Jin, Qi; Takahashi, Yoh-Hei; Amici, David R; Rendleman, Emily J; Rawat, Radhika; Bresolin, Silvia; Paganin, Maddalena; Zhang, Cheng; Li, Hu; Kandela, Irawati; Politanska, Yuliya; Abdala-Valencia, Hiam; Mendillo, Marc L; Zhu, Ping; Palhais, Bruno; Vlierberghe, Pieter Van; Taghon, Tom; Aifantis, Iannis; Goo, Young Ah; Guccione, Ernesto; Heguy, Adriana; Tsirigos, Aristotelis; Wee, Keng Boon; Mishra, Rama K; Pflumio, Francoise; Accordi, Benedetta; Basso, Giuseppe; Ntziachristos, Panagiotis
Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia. Journal Article
In: Cancer discovery, vol. 10, pp. 1388–1409, 2020, ISSN: 2159-8290.
@article{Zhou2020,
title = {Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia.},
author = {Yalu Zhou and Cuijuan Han and Eric Wang and Adam H Lorch and Valentina Serafin and Byoung-Kyu Cho and Blanca T Gutierrez Diaz and Julien Calvo and Celestia Fang and Alireza Khodadadi-Jamayran and Tommaso Tabaglio and Christian Marier and Anna Kuchmiy and Limin Sun and George Yacu and Szymon K Filip and Qi Jin and Yoh-Hei Takahashi and David R Amici and Emily J Rendleman and Radhika Rawat and Silvia Bresolin and Maddalena Paganin and Cheng Zhang and Hu Li and Irawati Kandela and Yuliya Politanska and Hiam Abdala-Valencia and Marc L Mendillo and Ping Zhu and Bruno Palhais and Pieter Van Vlierberghe and Tom Taghon and Iannis Aifantis and Young Ah Goo and Ernesto Guccione and Adriana Heguy and Aristotelis Tsirigos and Keng Boon Wee and Rama K Mishra and Francoise Pflumio and Benedetta Accordi and Giuseppe Basso and Panagiotis Ntziachristos},
doi = {10.1158/2159-8290.CD-19-1436},
issn = {2159-8290},
year = {2020},
date = {2020-01-01},
journal = {Cancer discovery},
volume = {10},
pages = {1388--1409},
abstract = {Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. SIGNIFICANCE: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery. .},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Lavaert, Marieke; Valcke, Brecht; Vandekerckhove, Bart; Leclercq, Georges; Liang, Kai Ling; Taghon, Tom
Conventional and Computational Flow Cytometry Analyses Reveal Sustained Human Intrathymic T Cell Development From Birth Until Puberty. Journal Article
In: Frontiers in immunology, vol. 11, pp. 1659, 2020, ISSN: 1664-3224.
@article{Lavaert2020,
title = {Conventional and Computational Flow Cytometry Analyses Reveal Sustained Human Intrathymic T Cell Development From Birth Until Puberty.},
author = {Marieke Lavaert and Brecht Valcke and Bart Vandekerckhove and Georges Leclercq and Kai Ling Liang and Tom Taghon},
doi = {10.3389/fimmu.2020.01659},
issn = {1664-3224},
year = {2020},
date = {2020-01-01},
journal = {Frontiers in immunology},
volume = {11},
pages = {1659},
abstract = {The thymus is the organ where subsets of mature T cells are generated which subsequently egress to function as central mediators in the immune system. While continuously generating T cells even into adulthood, the thymus does undergo involution during life. This is characterized by an initial rapid decrease in thymic cellularity during early life and by a second age-dependent decline in adulthood. The thymic cellularity of neonates remains low during the first month after birth and the tissue reaches a maximum in cellularity at 6 months of age. In order to study the effect that this first phase of thymic involution has on thymic immune subset frequencies, we performed multi-color flow cytometry on thymic samples collected from birth to 14 years of age. In consideration of the inherent limitations posed by conventional flow cytometry analysis, we established a novel computational analysis pipeline that is adapted from single-cell transcriptome sequencing data analysis. This allowed us to overcome technical effects by batch correction, analyze multiple samples simultaneously, limit computational cost by subsampling, and to rely on KNN-graphs for graph-based clustering. As a result, we successfully identified rare, distinct and gradually developing immune subsets within the human thymus tissues. Although the thymus undergoes early involution from infanthood onwards, our data suggests that this does not affect human T-cell development as we did not observe significant alterations in the proportions of T-lineage developmental intermediates from birth to puberty. Thus, in addition to providing an interesting novel strategy to analyze conventional flow cytometry data for the thymus, our work shows that the early phase of human thymic involution mainly limits the overall T cell output since no obvious changes in thymocyte subsets could be observed.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}