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Functional analysis of altered transcriptional pathways in diffuse large B-cell lymphoma of the ABC subtype

English title Functional analysis of altered transcriptional pathways in diffuse large B-cell lymphoma of the ABC subtype
Applicant Thome-Miazza Margot
Number 147620
Funding scheme Sinergia
Research institution Département de Biochimie Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Experimental Cancer Research
Start/End 01.01.2014 - 30.09.2017
Approved amount 1'500'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Molecular Biology

Keywords (3)

transcription factor; lymphoma; gene expression

Lay Summary (German)

Lead
In diesem Projekt untersuchen wir die molekularen Mechanismen der Entwicklung aggressiver B-Zell-Lymphome durch die Kombination von biochemischen und genetischen Methoden, um damit neue Ansätze für die Therapie und Diagnose dieser Lymphome zu entwickeln.
Lay summary

In dem vorliegenden Projekt untersuchen wir die molekularen Mechanismen der Entwicklung aggressiver B-Zell-Lymphome. Wir erforschen speziell das diffuse grosszellige B-Zell-Lymphom (DLBCL) vom aktivierten B-Zell (ABC) Typ, das durch einen aggressiven Krankheitsverlauf und eine schlechte Prognose charakterisiert ist. Tatsa¨chlich ko¨nnen gegenwa¨rtig nur ca. 50% der Patienten mit einer kombinierten Behandlung durch Chemotherapie und den Anti-CD20 Antiko¨rper Rituximab geheilt werden. Verbesserte therapeutische Strategien werden daher dringend beno¨tigt. ABC-DLCBL sind durch spezifische Vera¨nderungen in der Gentranskription gekennzeichnet. Ein besseres Versta¨ndnis dieser Vera¨nderungen ist Voraussetzung fu¨r die Entwicklung neuer therapeutischer Strategien. Wir wollen den Beitrag individueller Transkriptionsfaktoren zur Pathogenese dieser Lymphome in Zusammenarbeit erforschen, indem wir kombinierte biochemische und genetische Methoden einsetzen. Mit solchen synergistischen Ansa¨tzen sollen neue Gene und molekulare Mechanismen entdeckt werden, die spezifisch zur Entwicklung von ABC DLBCL beitragen. Diese Ergebnisse werden zum besseren Versta¨ndnis dieser Lymphome beitragen, und ko¨nnen ausserdem neue therapeutische und diagnostische Ansa¨tze erarbeiten.

Direct link to Lay Summary Last update: 01.11.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma.
Dai B. (2017), B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma., in Blood, 333.
Ets1 Phosphorylation at Thr38 (Pets1) Is Associated with Cell of Origin (COO), Cell Cycle Activation, and Inferior Outcome in Diffuse Large B Cell Lymphoma (DLBCL)
Chung E.Y. (2017), Ets1 Phosphorylation at Thr38 (Pets1) Is Associated with Cell of Origin (COO), Cell Cycle Activation, and Inferior Outcome in Diffuse Large B Cell Lymphoma (DLBCL), in Hematological Oncology (ICML Proceedings) , 56.
Mutational frequencies of CD79B and MYD88 vary greatly between primary testicular DLBCL and gastrointestinal DLBCL
Frick M. (2017), Mutational frequencies of CD79B and MYD88 vary greatly between primary testicular DLBCL and gastrointestinal DLBCL, in Leuk Lymphoma, 1.
Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL
Erdmann E. (2017), Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL, in Blood, 130, 310.
ETS1 Phosphorylation at Threonine-38 Is a Marker of B Cell Receptor Activation, Associating with Cell of Origin and Outcome in Diffuse Large B Cell Lymphoma.
Chung E.Y. (2016), ETS1 Phosphorylation at Threonine-38 Is a Marker of B Cell Receptor Activation, Associating with Cell of Origin and Outcome in Diffuse Large B Cell Lymphoma., in Blood (ASH proceedings), 1755.
The molecular pathogenesis of mantle cell lymphoma.
Vogt N., Dai B., Erdmann T., Berdel WE., Lenz G. (2016), The molecular pathogenesis of mantle cell lymphoma., in Leuk Lymphoma, Nov 28, 1-8.
The role of the CBM complex in lymphoid malignancies
Juilland M. and Thome M. (2016), The role of the CBM complex in lymphoid malignancies, in Curr. Opin. Hematol., 402.
Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma.
Weilemann A., Grau M., Erdmann T., Merkel O., Sobhiafshar U., Anagnostopoulos I., Hummel M, Siegert A Hayford C Madle H Wollert-Wulf B Fichtner I Dörken B Dirnhofer S Mathas S Janz M, Emre NC Rosenwald A Ott G Lenz P Tzankov A, Lenz G (2015), Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma., in Blood, 125, 124-132.
Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications.
Lenz Georg (2015), Insights into the Molecular Pathogenesis of Activated B-Cell-like Diffuse Large B-Cell Lymphoma and Its Therapeutic Implications., in Cancers (Basel), 811-822.
Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase.
Hailfinger S. Lenz G. and Thome M. (2014), Targeting B-cell lymphomas with inhibitors of the MALT1 paracaspase., in Curr. Opin. Chem. Biol. , 23, 47-55.
CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas.
Juilland M. Gonzalez M. Erdmann T. Banz Y. Jevnikar Z. Hailfinger S. Tzankov A. Grau, CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas., in Blood, pii: blood-2015-07-655647 [Epub ahead of print].
Ets1 Positively Regulates Faim3 in Activated B Cell-Like (Abc) Diffuse Large B Cell Lymphoma (DLBCL)
Priebe V., Ets1 Positively Regulates Faim3 in Activated B Cell-Like (Abc) Diffuse Large B Cell Lymphoma (DLBCL), in Hematological Oncology (ICML Proceedings) , 56.
Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas.
Bognar MK Vincendeau M Erdmann T Seeholzer T Grau M Linnemann JR Ruland J Scheel CH Lenz P, Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas., in Oncogene.
Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type
Priebe Valdemar, Sartori Giulio, NapoliSara, ChungElaine Yee Lin, CascioneLuciano, KweeIvo, ArribasAlberto Jesus, MensahAfua Adjeiwaa, RinaldiAndrea, PonzoniMaurilio, ZuccaEmanuele, RossiDavide, EfremovDimitar, LenzGeorg, ThomeMargot, BertoniFrancesco, Role of ETS1 in the Transcriptional Network of Diffuse Large B Cell Lymphoma of the Activated B Cell-Like Type, in Cancers, 12(7), 1912.

Collaboration

Group / person Country
Types of collaboration
Frank Rosenbauer, Universität Münster Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Urban Novak, Inselspital Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Maurilio Ponzoni, San Raffaele Scientific Institute Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Daniel Krappmann, Helmholtz Zentrum München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events



Self-organised

Title Date Place
Leukemia/Lymphoma Network meeting 21.06.2017 Epalinges, Switzerland
Leukemia/Lymphoma Network meeting 20.06.2014 Epalinges, Switzerland

Awards

Title Year
Jürg Tschopp Basic Life Sciences Award 2016

Associated projects

Number Title Start Funding scheme
150799 Advanced analysis of the function of single cells using flow imaging. 01.12.2013 R'EQUIP
166627 Identification et caractérisation de substrats de la protéase MALT1 01.05.2016 Project funding (Div. I-III)

Abstract

This project investigates the molecular mechanisms underlying the development of activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), an aggressive human lymphoma subtype characterized by poor patient outcome. Currently, only 50% of patients can be cured following a combined treatment with the B-cell depleting anti-CD20 antibody rituximab and the CHOP chemotherapy regimen (R-CHOP), underlining the need for improved therapeutic strategies. ABC DLBCLs are characterized by distinct transcriptional alterations; a better understanding of these is a prerequisite to develop novel therapeutic strategies. Here, we propose to elucidate the contribution of selected transcription factors to the molecular pathogenesis of this entity in a collaborative manner, using combined biochemical and genetic approaches. These synergistic approaches will unravel novel pathways and genes that specifically drive the development of ABC DLBCL and thereby lead to a significantly better understanding of the biology of ABC DLBCL. Moreover, they might identify novel therapeutic targets and generate diagnostic tools.
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