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Section des Unités de recherche

Report from the visiting committee

Research unit : Pathologie et Virologie Moléculaire

UMR 7151

University Denis Diderot – Paris 7

(2)

Section des Unités de recherche

Report from the visiting committee

Research unit :

Pathologie et Virologie Moléculaire

UMR 7151

University Denis Diderot - Paris 7

(3)

Report from the visiting committee

The research unit :

Name of the research unit : Pathologie et Virologie Moléculaire

Requested label : UMR CNRS, UMR_S INSERM

N° in case of renewal : 7151

Head of the research unit : Mr Hugues DE THE

University or school :

University Paris 7 – Denis Diderot

Other institutions and research organization:

INSERM

CNRS

Date(s) of the visit :

January, 25th of 2008

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Members of the visiting committee

Chairman of the commitee :

Mr Alain ISRAEL, Paris

Other committee members :

Mr Arthur ZELENT, London, UK

Mr Bohdan WASYLYK, Nantes Mr Hinrich GRONEMEYER, Strasbourg Mr Gilles FAVRE, Toulouse

Mr Sophie EZINE, Paris

CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD…

representatives :

Mr Marc SITBON : CoNRS representative

Mr Nicolas JEANJEAN, CSS INSERM representative Mrs Sylvie van der WERF, CNU representative

Observers

AERES scientific representative:

Mr Pierre CHARDIN

University or school representative:

Mrs Sylvie VAN DER WERF, University representative

Research organization representative (s) :

Mrs Evelyne MARCHE, CNRS

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Report from the visiting committee

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Short presentation of the research unit

• Numbers of researchers with teaching duties : 7

• Numbers of full time researchers (INSERM, CNRS…) : 12

• Number of enginneers, technicians and administrative assistants : 13

• Numbers of PhD students : 14, all of them with funding

• Numbers of HDR : 15 including 5 who are PhD advisor

• Number of lab members who have been granted a PEDR : 1

• Numbers of PhD students who have obtained their PhD since 2004 : 14

• Average length of a PhD during the past 4 years : 3 years

• Number of publishing lab members : 19 out of 19

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Preparation and execution of the visit

The visit started with a general introduction by the head of the Unit in the presence of the PI’s. Then the individual subgroups presented their projects : 75 min for team 1, 30 min for team 2, 20 min for team 3, 30 min for team 4, 30 min for team 5 and 55 minutes for team 6. The committee then visited the labs and the posters (45 min), and met with the recently created conseil de laboratoire. Finally the committee met in private session for 1h30. This was followed by a brief report by the chairman to the lab members.

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Overall appreciation of the activity of the research unit, of its

links with local, national and international partners

The general impression was very positive. At the origin the Unit was based on 2 projects, pathogenesis of Acute Promyelocytic Leukemia (APL), and retrovirology. It evolved with the adjunction of two teams whose expertise is centered around normal and pathological T cells, and a relatively recent reconsideration by the team lead by the haed of the unit of the role of p53 in breast cancer. This gives rise to a strong portfolio of fondamental research into various cancer pathologies, supported by fundamental studies and closely associated with the clinic, a mix which is not so frequently encountered. Internal collaborations between subgroups are favored by the general context of the Unit. It is clear that the Unit plays an important role in the context of the Saint-Louis campus, exemplified by the role of one of the team leader who is also the head of the Institute’s chromosome profiling platform. The Unit has strong links with the hospital, with the pathology dept, as well as with other research units on the campus (regular lab meetings with 2 other groups).

National collaborations are also well developped, in the context of various newtworks such as Canceropole Ile de France, REMAGUS network, a consortium on animal cancer models, and collaboration with Institut Pasteur on retrovirology. From an international point of view, collaborations also seem to be excellent :formal links have been established with Lebanon, UK, Germany, and most importantly, China (10 years-old collaboration with a group in Shangai, including 2 scientists formally linked through CNRS to the Paris Unit). The Unit is also part of an EC FP6 EPITRON (Epigenetic treatment of neoplastic disease

)

consortium.

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Specific appreciation team by team and/or project by

project

Team 1 : APL

The head of this team has had a long standing interests in the pathogenesis and therapy of acute promyelocytic leukaemia and function of the PML protein as well as PML associated nuclear bodies. Over the past 5 years, which were reviewed during this Site Visit, his laboratory has maintained the highest standard of national and international standing in these fields. This is reflected by multiple original publications in very high impact journals, such as Cancer Cell, PNAS, J. Exp. Med., reviews in Nature Reviews of Cancer and a Cell editorial. The international recognition of the team leader is underscored by invitation to multiple international meetings and membership on editorial boards (Cancer Research, for example). During the review, the team leader referred to key accomplishments that included demonstration that APL responds synergistically to all-trans-retinoic acid (ATRA) plus Arsenic (As), a combination highlighted by a basic observation that both ATRA and As degrade PMNL-RARA. His laboratory demonstrated this therapeutic synergy in the animal model of APL and the positive results of these studies lead to a number of international clinical trials. His laboratory has also demonstrated requirement of RXR for PML-RARA function and in most recent and yet unpublished work described APL stem cells and their sensitivity to combination of ATRA and cAMP or phosphodiesterase (PDE) inhibitors. The work that this team has carried out on APL demonstrate one of the best examples of translational cancer research and carries potential relevance to other neoplastic diseases. Hugues de Thé’s basic work on the function of PML has also been very successful. In this area his laboratory has helped to understand the role of sumoylation and sumo interaction domains (SIM) in the assembly of PML nuclear bodies and the role of sumoylation in the degradation of the PML as well as PML-RARA protein. On a number of occasions, results from his laboratory have clarified some contentious issues in the field. For the future, the team leader envisages that considerable work remains in the APL field, particularly with respect to identification of targets of PML-RARA and further characterisation of APL stem cell and their sensitivities to combinations of ATRA, As and PDE inhibitors. In his view combination of these agents would constitute the most ideal form of anti-APL therapy. He has recently obtained mice that lack expression of various RXR genes from a laboratory in Strasbourg that will now be used to explore further the requirement of RXR for APL development due to PML-RARA expression. These are all important studies that should lead to results with a major impact on the APL field. As in many other instances it is likely that results obtained in APL model will extend to other haematopoietic neoplasms. In conclusion his group has been highly productive leading to results of consistently excellent quality and there is every indication that this high level of science will continue in the future.

Team 2 : Breast cancer

The projects aim to define new molecular profiles of breast cancer tissue in order to predict therapeutic response or prognosis. The first part will define the role of p53 status in the response to adjuvant therapy in a large cohort of 350 breast cancer patients using the yeast functional assay. The association with the estrogen receptor (ER) status will also be determined. This work is based on data published in Lancet (2002) and Plos Med (2007). While many studies have been published on the role of p53 mutations in breast cancer progression and therapeutic response, no clear conclusion concerning the use of this parameter in patient care has been reached. The originality of this project is the technical approach, and it deserves support. In basal breast cancer the aim is to determine whether “unfolded” p53 mutants interfere with normal p63 function, and whether this association leads to a dominant negative effect on p63-dependent epithelial differentiation. This project associates studies on breast cancer tissues and on mouse in vivo models. This approach bears similarity to the work on PML/RAR, which is a proof of feasibility.

The second part refers to the fine characterization of the ER status in breast cancer using a combination of approaches : IHC, transcriptome, determination of splice variants of the ER… This is not a new question, and many publications have addressed this question. However there are ER-positive patients for whom it is difficult to prevent anti hormonal therapeutic response, or ER-negative patients who could benefit from anti hormonal therapies. This project could bring some new responses to this field. In conclusion, this project aims to revisit old questions by using new technical approaches or by integrating new knowledge. It uses the recipes that have been successful for the PML/RAR project, based on a permanent to-and-fro movement between basal and translational research. However breast cancer research is highly competitive, and maintaining a standard similar to that of the PML/RAR project will require a continuous effort.

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Team 3 :

The leader of this team had a productive postdoc resulting in one major publication, one other high impact publication as second to last author, and a patent. He also presented his work at several international conferences, and in seminars at a number of institutes, mainly in France. He founded a small group that benefited from Avenir as well as other grants as start-up funding. More recently, about one year ago, the team leader joined the unit to establish his independence. This is a positive move, which will give the team leader an additional opportunity to evolve and synergise with other groups in a dynamic and productive environment that is addressing both related and more distant research topics. He will have the benefit of « distant » mentoring by senior members of the Unit and particularly the head of the unit. His research will help strengthen the breast cancer part of team 1. The publication record of the team leader is relatively limited over the last four years, which is not to be unexpected for a scientist establishing his own group. The projects undertaken by the team leader have the potential to be fruitful in the near future. He has continued characterising NFAT factors in breast cancer cell lines and is generating animal models. This is an interesting field for study. The most promising findings appear to be the chip-on-chip and transcriptomic microarray analysis of NFAT regulated genes potentially involved in invasion as opposed to migration (as defined in in-vitro assays). Several genes have been chosen for detailed analysis, based mainly on their known potentially relevant functions. There are potentially promising findings for one of them. The major challenge will be to extend these findings to more refined analysis of the mechanisms and to animal models, and to relate these findings to human tumours. Expertise is available in the group and unit, and more detailed studies could benefit from outside collaborations. Several other projects are still in their early stages, particularly the transgenic mouse models of NFAT driven tumorigenesis in the breast and the role of sumoylation in the regulation of NFAT5 stability. This team is small and relatively “young”: 2 PhD students, one first post-doc and a junior level technician. Progression to independence will require publication and obtaining funding. The current politics of sharing funding and resources in the group and unit is envisaged to be important for this young investigator, to help bridge this potentially difficult endeavour, and to progress to independence.

Team 4 :

Thie team joined the unit in 2002. It originally started with the identification of dendritic cell (DC) progenitors in the cord blood. This study led to the identification of a hematopoietic population with strong NK activity; indeed, the bipotent progenitor NK/DC could also give rise via a TGF 1-independent and M-CSF resistant pathway to Langerhans cells. Recently, the team reconsidered the early stages of human lymphoid ontogeny. The team has achieved a pioneer work in the field of human hematopoiesis by identifying a major subset of T cell progenitor, present in the cord blood and the bone marrow. This has led to a paper in Immunity in 2006. The team leader obtained his MD in 1992 and his PhD in 1996. He is a professor at the EPHE since 2005 and teaches about 50 hours/y, but was since 1999 involved in the Immunology Training Course. He works with 2 PhD students and a graduate student together with 1 technician and an assistant-engineer. He recently recruited a MCU. The scientific production of the team has been very good. The team leader is senior author in 5 publications (Blood, J Virology, Immunity) since 2002. He is the laureate of a 5-year Contrat Avenir Inserm since 2007 and has obtained numerous grants (Fondation de France, LNCC, ARC) which reveal the autonomy of the team and the strong maturity of the project. The current project of the team is focused on the identification of the molecular players involved in the commitment of early lymphoid progenitors towards the T cell lineage, and on the search for their possible contribution to the pathophysiology of T-acute lymphoblastic leukaemia (T-ALL). It is based on comparative transcriptome analysis of the recently identified fetal prethymocytes with a series of post-natal thymocytes corresponding to successive well- defined T cell differentiation stages. They have now identified 2 molecules whose characterisation and role in T cell commitment is being investigated. One of them promotes T cell development while the other seems to be involved in the Wnt/beta-catenin pathway. In vivo approaches (conditional invalidation of the genes) and in vitro studies are planned. The program of the team is ambitious and competitive at the international level. Because the size of the lab is moderate, the project has been restricted to the characterisation of the 2 recently identified proteins, which will require a collaborative effort. Regarding the ultimate goal which is to provide an accurate description of the networks that control the early stages of T cell development, the team needs to hire more people to remain competitive.

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Team 5 :

This small team includes 3 MD/PhD, 2 PhD students and 3 technicians belonging to the core facilities of the Saint Louis campus. Recruitment of a post-doc is planned. Despite the relatively small size of the group, they have been able to generate and publish data of a high international standard (several recent publications in Blood) regarding the genetics and oncogenesis of T-ALL. They have developped systematic genomic strategies to discover genomic abnormalities in T-ALL, and have discovered several new T-ALL categories that target genes such as c-Myb, HOXA and cyclin D2. The strength of this group lies in the connection with clinicians of the Saint Louis campus, which allows them to have access to a large number of carefully annotated tumor cells. Another strength is the easy access to a well equipped high throughput genomic facility (JS is the head of the Chromosome Profiling Facility). In the future they plan to (1) identify new genomic rearrangements associated with currently « orphan » T-ALL cases : this will follow the procedure they have used before and should most likely lead to the identification of new target genes., (2) generate animal models of T-ALL based on the oncogenes they have already identified : this is an important project that differentiates the research performed by this group from the other groups that study the genetics of T-ALL. These projects are encouraged. (3) participate, in collaborations with the clinicians, in the classification of T-ALL based on either rearrangment of the c-Myb locus, or on a more general transcriptome analysis. This should allow to attribute a pronostic value to each category of T-ALL.

Team 6 :

The team leader is Professor at the University Paris 7. The team also includes 1 senior scientist, 1 post-doctoral fellow, 2 PhD students (4th and 1st year) and 1 technician. It will be joined by another senior scientist in September 2008. This team works on two retroviruses: primate foamy viruses (PFV) and HIV. A third model on Ty1 yeast transposon will be added (Primate foamy viruses). The team has developed a world recognized expertise in the study of latency and the opposing effects the Tas (lysis-associated) and Bet (persistence-associated) viral proteins. A striking achievement has been obtained in collaboration on the blockade of anti miRNA-mediated silencing by Tas (Science, 2005). They extended their initial observation on the association of entering particles with the Microtubule Organizing Center to show that upon entry into resting cells, foamy virus capsids accumulate in close proximity of the centrosomes where decapsidation can be paused for several weeks before reactivation of the infectious cycle (PLoS Pathogens, 2007). Most recently, they have discarded a role of the viral protease in the late decapsidation step and shown DNA-tethering properties of foamy Gag proteins. Most recently, this team has also shown that upon entry into resting cells, HIV preintegration complexes accumulate in close proximity of the centrosomes, where the replication cycle can resume upon activation of the cell cycle (Retrovirology, 2007). Future prospects include the morphological studies of paused viral complexes, and phosphorylation of HIV CA by cell cycle kinases, as well as the role of Gagp6 and SUMO-1 conjugates during these steps.

The team leader has developed an outstanding effort of communication towards the general public on the biology of viruses and their potential beneficial use. He was granted the 2007 EMBO award for communication in Life Sciences. His production includes an internationally prized documentary, public meetings and didactic interviews with major national media (TV and magazines). Despite its small size, this team has shown a marked international leadership in the study of the early replication stages of primate foamy viruses and has successfully extended its themes to HIV. The project to integrate the Ty1 model in the team with the upcoming arrival of a senior scientist will be beneficial for the dynamics of the group and promises productive interactions between the three models.

5

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Appreciation of resources and of the life of the research unit

Of the quality of the management : excellent.

Of human ressources : excellent.

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6

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Recommendations and advice

Strong points :

Strong association between fondamental and clinical research, and strong links with clinic. Some relatively unorthodox hypotheses.

What needs to be improved :

Some teams may be too small. The projects require a P3 facility with a FACS. The team would also benefit to have more technicians with a tenured position.

Recommendations :

It is highly likely that the repertoire of genes studied by two of the teams will overlap. Formal collaboration between these 2 groups should be encouraged, as they use complementary approaches and would undoubtedly benefit from exchanging techniques and information. Similarly team 1 and team 3 should develop interactions. More generally the small size of certain groups might be compensated at least in part by developing internal collaborations ; in this respect, the next 4 years will be critical.

The visiting committee was favorably impressed by the quality of the research in the unit and considers it is among the top 15% in its field.

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References

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