Fondation MEDIC

www.fondation-medic.ch

Characterization of molecular biomarkers relevant to the biology, diagnosis and prognosis of peripheral T-cell lymphomas
[13.09.2015]
Project leader – Laurence de Leval
Laurence de Leval

Laurence de Leval obtained her MD degree in July 1994 at the University of Liège Summa cum laude. In 1998 she earned a PhD in Biomedical Sciences at the University of Liège. She passed The United States Medical Licensing Examination in 1999 and became Board certified in Pathologic Anatomy and Cytology in 2000. In 2007 she earned the Agrégation de l’Enseignement Supérieur at the University of Liège.

Her research training included a Research Fellowship of the Belgian National Fund for Scientific Research (FNRS) from 1994-1998 and between 1998-1999 a post-fellowship in Hematopathology at Harvard medical
School, Boston. From 2000-2002 she was staff member, Department of Pathology, CHU Sart Tilman and from 2002-2006 Associate Laboratory Director, Department of Pathology, CHU Sart Tilman and since2006 Director.

In 2007 she became Permanent Research Associate of the FNRS, in 2008 Clinical Professor of Pathology, University of Liège and in 2009 Professeur Ordinaire and chef de service of clinical pathology at CHUV, Lausanne.

University Institute of Pathology CHUV
Service de Pathologie Clinique
Rue du Bugnon 25
CH-1011 Lausanne

E-Mail: laurence.deleval@chuv.ch

Group members
 

Mauro Delorenzi PhD

senior scientist

Eduardo Missaglia PhD

bioinformatician

Pamela Dobay PhD

postdoctoral fellow

Philippe Gaulard MD

senior scientist

Bettina Bisig MD

clinician scientist

Project description
 

Peripheral T-cell lymphomas (PTCLs) (i.e. neoplasias derived from mature T and NK cells) are a heterogeneous group of rare diseases, accounting for less than 10% of all lymphomas. These cancers pose several challenges: most exhibit resistance to classical polychemotherapy regimens and have a poor prognosis; their pathological diagnosis of PTCLs is often difficult, and the genetic alterations underlying their pathogenesis are largely unknown; and research in the field of PTCLs has been hampered by the absence of cell lines representative of the major entities, and the lack of good animal models. (1) Our works over the past few years have contributed to the understanding of the pathobiology of some of these disease entities (2-4); in particular we showed that angioimmunoblastic T-cell lymphoma (AITL), which is one of the most common disease entities, is derived from a peculiar T-cell subpopulation, namely follicular helper T cells, and our studies highlighted some overlap between AITL and another entity named PTCL, not otherwise specified (PTCL, NOS).(2,5) The molecular mechanisms driving TFH oncogenic transformation remain largely unknown.(6-8)

Our ongoing project aiming at gaining novel insights into the molecular classification of PTCLs, relies on an integrated strategy analysing genomic alterations, mRNA and mi-RNA profiles, and epigenetic alterations of a large collection of PTCLs with frozen tumor samples (approx. 300 cases), collected in the frame of a multicentric consortium (France, Belgium and Switzerland). A large number of reactive lymphoid tissues and various sorted T-cell populations are also used as controls for comparison. We expect that the combination of overall gene expression patterns and (epi)genetics will improve their biomolecular classification and should identify clinical traits that will allow therapeutic stratification. Specifically, the following questions are being addressed:

  • What are the oncogenic mechanisms underlying PTCL pathogenesis?
  • Can molecular profiles improve the classification of PTCLs?
  • Are molecular signatures associated with distinct clinical traits, prognoses and/or response to treatment?
  • Can these molecular studies help to characterize new potential therapeutic targets and be used as a rationale for specific therapies?

figure 1

Publications
 
2014 / doi: 10.1182/blood-2014-07-584953. PMID: 25224410
Bossard C, Dobay MP, Parrens M, Lamant L, Missiaglia E, Haioun C, Martin A, Fabiani B, Delarue R, Tournilhac O, Delorenzi M, Gaulard P, de Leval L. Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation between protein and mRNA expression. Blood. 2014 Nov 6;124(19):2983-6.
» PubMed
2013 / 10.1371/journal.pone.0064536
Auguste T, Travert M, Tarte K, Amé-Thomas P, Artchounin C, Martin-Garcia N, de Reynies A, de Leval L, Gaulard P, Delfau-Larue MH. ROQUIN/RC3H1 alterations are not found in angioimmunoblastic T-cell lymphoma. PLoS One 2013;8:e64536
» PubMed
2012 / doi: 10.1182/blood-2011-12-396150
Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau-Larue MH, Berger F, Bosq J, Brière J, Soulier J, Macintyre E, Marafioti T, de Reyniès A, Gaulard P. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood. 2012;119:5795-806
» PubMed
2012 / Blood. 2012;120:1466-9
Lemonnier F, Couronné L, Parrens M, Jaïs JP, Travert M, Lamant L, Tournillac O, Rousset T, Fabiani B, Cairns RA, Mak T, Bastard C, Bernard OA, de Leval L, Gaulard P. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. doi: 10.1182/blood-2012-02-408542
» PubMed
2012 / doi: 10.1016/j.beha.2012.01.004
Bisig B, Gaulard P, de Leval L. New biomarkers in T-cell lymphomas. Best Pract Res Clin Haematol 2012;25:13-28
» PubMed
2012 / 10.1111/j.1365-2559.2011.04022.x
Bisig B, Thielen C, Herens C, Gofflot S, Travert M, Delfau-Larue MH, Boniver J, Gaulard P, de Leval L. c-Maf expression in angioimmunoblastic T-cell lymphoma reflects follicular helper T-cell derivation rather than oncogenesis. Histopathology. 2012 Jan;60(2):371-6
» PubMed
2012 / 10.1182/blood-2011-11-391748
Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, Parrens M, Martin A, Xerri L, Brousset P, Chan LC, Chan WC, Gaulard P, Mak TW. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012 Feb 23;119(8):1901-3
» PubMed
2012 / 10.1182/blood-2012-02-408542
Lemonnier F, Couronné L, Parrens M, Jaïs JP, Travert M, Lamant L, Tournillac O, Rousset T, Fabiani B, Cairns RA, Mak T, Bastard C, Bernard OA, de Leval L, Gaulard P. Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters. Blood. 2012 Aug 16;120(7):1466-9
» PubMed
2012 / 10.1182/blood-2011-12-396150
Travert M, Huang Y, de Leval L, Martin-Garcia N, Delfau-Larue MH, Berger F, Bosq J, Brière J, Soulier J, Macintyre E, Marafioti T, de Reyniès A, Gaulard P. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets. Blood. 2012 Jun 14;119(24):5795-806
» PubMed
2011 / 10.1111/j.1365-2559.2010.03704.x
de Leval L, Gaulard P. Pathology and biology of peripheral T-cell lymphomas. Histopathology. 2011 Jan;58(1):49-68
» PubMed
2010 / 10.1111/j.1365-2141.2009.08003.x
de Leval L, Gisselbrecht C, Gaulard P. Advances in the understanding and management of angioimmunoblastic T-cell lymphoma. British Journal of Haematology 2010 Mar;148(5):673-89
» PubMed
2010 / 10.1182/blood-2009-05-221275
Huang Y, de Reyniès A, de Leval L, Ghazi B, Martin-Garcia N, Travert M, Bosq J, Brière J, Petit B, Thomas E, Coppo P, Marafioti T, Emile JF, Delfau-Larue MH, Schmitt C, Gaulard P. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010 Feb 11;115(6):1226-37
» PubMed
2007
de Leval L, Rickman DS, Thielen C, Reynies Ad, Huang YL, Delsol G, Lamant L, Leroy K, Brière J, Molina T, Berger F, Gisselbrecht C, Xerri L, Gaulard P. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood. 2007 Jun 1;109(11):4952-63
» PubMed