Institut Universitaire d'Hématologie / IFR 105

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Curriculum Vitae

Hugues de THE

Born January 18, 1959 in Marseille (France).
Lab address: CNRS UMR 7151 Hopital St Louis Paris (+331) 57 27 67 70, Fax (+331) 57 27 67 95
mail: dethe@univ-paris-diderot.fr

HIGHER EDUCATION

Medical training
1978-1984 Universities of Lyon and Paris (Hopital Necker)
1984-1988 Residency (specialty: medical research) and doctor in Medicine. Paris

Biology training
1984 Graduation "Biologie cellulaire et moléculaire"
1986 Course of general virology, Institut Pasteur Paris
1989 Ph.D. University of Paris

LABORATORIES

1985-1991 Pr. Tiollais / Dr. Dejean (doctoral and post-doctoral work, retinoic acid receptors) Institut Pasteur
1991- Group head -CNRS 43 Hopital St. Louis Paris
1996- Lab head- CNRS UMR-7151 Hopital St. Louis Paris

APPOINTMENTS

1984-1988 Resident, Paris Hospitals
1990 Lecturer in Biochemistry, University of Paris VII
1990 Staff scientist at INSERM
1993 Director of research at INSERM
1995 Professor of molecular biology, University of Paris medical school

CURRENT POSITIONS

2003 President of the scientific council of ARC
2003 Associate editor, Cancer Research
2004 Member of EMBO

AWARDS

1991 Prix Yvelines (LNCC)
1992 Prix B. Halpern
1996 Prix R. Mandé (Académie de Médecine)
1999 Prix Rosen (FRM)
2002 Prix Etancelin (French Academy of Sciences)
2003 Prix Paris (LNCC)
2004 Prix Mergier-Bourdeix (French Academy of Sciences)

Hugues de THÉ Professor
Elisabeth TURPIN MCU Paris 7
Valérie LALLEMAND-BREITENBACH CR2 INSERM
Dominique VITOUX PH AP-HP
Marie-Claude GUILLEMIN CR1 INSERM
Morgan LE BRAS MCU P7
Rihab NASR Post-Doc (bourse Eli Lilly)
Antoine PASCAUD-OUVRARD Post-Doc (Bourse CEE)
Mehdi BOUROUBA Post-Doc Paris 7
Marion JEANNE PH.D. STUDENT (bourse MRT)
Laurent PERES Technician CNRS
Nicole HONORE Senior Technician Paris 7
Hassan SOIHILI Technician CNRS
Caroline BERTHIER Technician Paris 7
Macarena ROBLEDO Contractual technician Paris 7

SUMMARY OF PREVIOUS WORK

Acute promyelocytic leukemia is characterised by a specific t(15 ;17) translocation and an exquisite sensitivity to both retinoids and arsenic trioxide. Both of these agents induce differentiation or apoptosis of the leukemic cells in vivo. In 1990, in collaboration with A. Dejean, I showed that this translocation fuses the PML and the RAR gene to generate a PML/RAR fusion protein, identifying the first recurrent alteration of a nuclear hormone receptor in a human cancer. This fusion protein was shown to be both the trigger for leukemogenesis, presumably through interference with target genes implicated in myeloid differentiation, but also for therapeutic response. Our work allowed the use of molecular tool for the diagnosis and follow-up of patients. Since retinoic acid obviously targets the oncoprotein, acute promyelocytic leukemia became the first example of both differentiation therapy and oncogene-targeted anticancer treatment.

My group first identified the association of the PML protein with a subnuclear domain and showed that PML/RAR expression disrupts this domain. This change in PML distribution is associated to a sharp apoptosis resistance, but is reversible upon administration of the two therapeutic agents. PML nuclear bodies have drawn considerable attention due to their links, only partially understood, with transcription control, senescence and viral infections. Disruption of PML bodies is a now classical example of the links between altered nuclear architecture and diseases. This specific distribution of PML can be used for the diagnosis of PML//RAR associated leukemias.

In 1995, arsenic was shown to be a potent agent in the treatment of APL. We have shown that arsenic, like retinoic acid, induced the reaggregation of nuclear bodies and the specific degradation of PML/RAR We have demonstrated that retinoic acid-induced PML/RAR degradation involves the proteasome the RAR moiety of the fusion. Within RAR , we showed that the AF-2 transcriptional activation region is absolutely required for catabolism, unexpectedly linking receptor catabolism to transcriptional induction. Conversely, we have shown that arsenic-induced PML/RAR catabolism involves the PML moiety of the fusion protein and absolutely requires a specific sumolation site, identifying the first setting where protein sumolation directly or indirectly favours its catabolism. This work on PML sumolation allowed us to define the intranuclear traffic of PML and to suggest an implication of PML nuclear bodies in proteolysis. Hence, these two therapies directly target the oncogene to the proteasome through defined and functionally relevant domains in the RAR part for retinoic acid and in the PML part for arsenic.

Retinoic acid resistant cells are sensitive to arsenic trioxide and vice versa. We have identified a major synergy between these two agents ex vivo or in transgenic models of the disease. Combined treatments in mice yield complete remissions and the eradication of the leukemic clone. Our results have opened the way to trials associating the two agents in leukemia patients. In fact, the Shanghai group has recently shown that induction regimen associating the two drugs leads to a faster leukemia clearance than either drug alone, corroborating the results obtained with the mice. We have also used this model to directly establish that cAMP signalling can promote differentiation and apoptosis in vivo. Moreover, in a RA and arsenic resistant APL patient, inhibitors of cAMP degradation triggered leukemia differentiation and disease clearance. Thus, this model can not only be used to assay new therapeutic schemes using known drugs, but also to screen new drugs, that later turn to be active in patients.

Breast cancer is another example of a malignancy associated to nuclear hormone receptors. In line with our APL work, we have started investigating some aspects of breast cancer response to therapies. Analysing response of breast cancer patients to chemotherapy, we have demonstrated that a mutation in the P53 tumour suppressor gene is highly predictive of tumour clearance. As in leukemias, this could lead to treatment tailoring on the basis of underlying genetic defects.

In summary, for the 15 past years, our work has uncovered the first model of rational anticancer agents directly targeted at the underlying genetic lesions and have allowed very significant progress in the management of the patients.

CURRENT INTERESTS

The group develops a number of approaches aimed at further understanding the pathogenesis of acute promyelocytic leukemia, in particular the molecular bases of its response to retinoic acid, arsenic and cAMP. This is essentially achieved through the analysis of the phenotype and transcriptome of cells or animals expressing PML/RARA mutants.

Another goal of the lab is to understand the role of PML, the partner of RARA in APL. PML organizes nuclear structures of unknown function, PML nuclear bodies. Upon its modification by the ubiquitin-like peptide SUMO, PML recruits a variety of proteins onto these domains. Using a variety of cell biology approaches we are investigating the formation and role of this domains, with reference to APL, where they are disrupted in a therapy-reversible manner.

The last part of our interest is translationnal research in the field of breast cancer. We are interested in the molecular determinants for the response to neo-adjuvant chemotherapy. The TP53 status appears to be a critical determinant of complete response to high dose anthracyclin/ cyclophosphamide therapy. We are further investigating the determinants for this response, which could yield novel indications on a molecular classification of breast cancers.

MAJOR PUBLICATIONS

Warrell, R., de Thé, H., Wang Z. and Degos L. (1993) Acute promyelocytic leukemia: recent advances in biology and treatment. N. Engl. J. Med. 329, 177-189.

Daniel MT, Koken M, Romagné O, Barbey S, Barzarbachi A, Stadler M, Guillemin MC, Degos L, Chomienne C, de Thé H. (1993) PML expression in haematopoietic and APL cells. Blood 82, 1858-1867.

Saib A, Peries J, de Thé H. A defective human foamy virus generated by pregenome splicing (1993) EMBO J 12, 4439-4444.

Bazarbachi A, Saal N, Laroche L, Flageul B, Peries J, de Thé H. (1993) Absence of HTLVI sequences in cutaneous lesions of patients with Mycosis Fungoides and Sezary Syndromes. Science 259, 1470-1471.

Koken M, Puvion-Dutilleul F, Viron A, Stuurman N, Szostecki C, Chomienne C, Degos L, Puvion E, de Thé H. (1994) The t(15,17) translocation alters the structure of a nuclear body in a RA-reversible fashion EMBO J 13, 1073-1083.

A. Saib, J. Peries, H. de Thé. (1995) Involvement of a spliced and defective human foamy virus in the establishment of chronic infection J. Virol.69, 5261-5268

Zhu, J., Koken, M., Quignon, F., Chelbi-Alix, M., Degos,L., Wang,Z.Y., Chen, Z., de Thé,H. (1997) Arsenic-induced PML targeting onto nuclear bodies, implications for the treatment of acute promyelocytic leukemia. PNAS 94, 3978-3983.

Saib, A, Puvion, F, Schmid, M, Periès, J. de Thé, H. (1997) Nuclear targeting of incoming human Foamy virus involves a centriolar step. J. Virol. 71, 1155-1161.

Gianni, M., Koken, M., Chelbi-Alix, M., Benoit, G., Lanotte, M., Chen, Z., and de Thé, H. (1998). Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic resistant NB4 cells. Blood 91, 4300-4310.

Quignon, F., De Bels, F., Koken, M., Feuteun, J., Ameisen, J. C., and de Thé, H. (1998) PML triggers a caspase independent cell death process. Nature Genetics 20, 260-265.

Lallemand, V. Guillemin, M.C., Janin, A., Daniel, M.T., Degos, L., Kogan, S., Bishop, M. and de Thé, H. (1999) Retinoic acid ans arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J. Exp. Med. 189, 1043-1052.

Zhu, J. Gianni, M, Honore, N., Kopf, E., Chelbi-Alix, M., Koken, M., Quignon, F., Rochette-Egly, C., de Thé, H., (1999) Retinoic acid induces proteasome-dependent degradation of RAR and oncogenic RAR fusion proteins PNAS 96, 14807-14812.

Bazarbachi, A., El.Sabban, M., Nasr, R., Quignon, F., Awaraji, C., Kersual, J., Dianoux, L., Zermati, Y., Haidar, J., Hermine, O., and de Thé, H. (1999) Arsenic trioxide and interferon a synergize to induce cell cycle arrest and apoptosis in HTLVI-transformed cells. Blood, 93, 278-283.

Lallemand, V., Zhu, J., Puvion, F., Koken, M., Honoré, N., Doubeikovski, A., Duprez, E., Pandolfi, P.P., Puvion, E., Freemont, P., de Thé, H. (2001) Role of PML sumolation in nuclear body formation and As2O3-induced PML or PML/RARa degradation. J. Exp. Med. 193, 1361-1371.

Zhu, J, Chen, Z., Lallemand-Breitenbach, V., de Thé, H. (2002) How acute promyelocytic leukemia revived arsenic Nature Reviews on Cancer, 2, 705-709.

Bertheau P, Plassa F, Espié M, Turpin E, de Roquancourt A, Marty M, Lerebours F, Beuzard Y, Janin A, de Thé H (2002) Response of TP53 mutant breast cancers to high dose chemotherapy The Lancet 360, 852-854.

GuilleminMC, RaffouxE, VitouxE, Kogan S, SoihiliH, Lallemand-BreitenbachV, ZhuJ, JaninA, DanielMT, GourmelB, DegosL, DombretH, Lanotte M, de Thé H (2002). In vivo activation of cAMP signaling induces growth arrest and differentiation in acute promyelocytic leukemia J. Exp. Med. 196, 1373-1380.

Nasr, R., Rosenwald, A., El-Sabban, M. E., Arnulf, B., Zalloua, P., Lepelletier, Y., Bex, F., Hermine, O., Staudt, L., Bazarbachi, A., de The, H. (2003). Arsenic/interferon specifically reverses 2 distinct gene networks critical for the survival of HTLV-1-infected leukemic cells. Blood 101:4576-4582.

Shen, Z. X., Shi, Z. Z., Fang, J., Gu, B. W., Li, J. M., Zhu, Y. M., Shi, J. Y., Zheng, P. Z., Yan, H., Liu, Y. F., de Thé, H., Wang, Z.Y. et al. (2004). All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 101, 5328-5335.

Kamashev, D. Vitoux, D., de Thé H (2004) PML/RARA-RXR oligomers mediate retinoid- and rexinoid- /cAMP cross-talks in APL cell differentiation J. Exp. Med. 199, 1-13.

Takahashi Y, Lallemand-Breitenbach V, Zhu J, de The H. PML nuclear bodies and apoptosis. Oncogene. 2004;23(16):2819-24. Review.

Zhu J, Zhou J, Peres L, Riaucoux F, Honore N, Kogan S, de The H. A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell. 2005 ;7(2):143-53.

Lehmann-Che J, Giron ML, Delelis O, Lochelt M, Bittoun P, Tobaly-Tapiero J, de The H, Saib A. Protease-dependent uncoating of a complex retrovirus. J Virol. 2005 Jul;79(14):9244-53.

Nasr R, El-Sabban ME, Karam JA, Dbaibo G, Kfoury Y, Arnulf B, Lepelletier Y, Bex F, de The H, Hermine O, Bazarbachi A. Efficacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene. 2005 Jan 13;24(3):419-30.

Kfoury Y, Nasr R, Hermine O, de The H, Bazarbachi A. Proapoptotic regimes for HTLV-I-transformed cells: targeting Tax and the NF-kappaB pathway. Cell Death Differ. 2005 Aug;12 Suppl 1:871-7. Review.

Altucci L, Rossin A, Hirsch O, Nebbioso A, Vitoux D, Wilhelm E, Guidez F, De Simone M, Schiavone EM, Grimwade D, Zelent A, de The H, Gronemeyer H. Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res. 2005 Oct 1;65(19):8754-65.

Lallemand-Breitenbach V, Zhu J, Kogan S, Chen Z, de The H. Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia. Nat Rev Cancer. 2005 Oct;5(10):821-7. Review.

Nasr R, Chiari E, El-Sabban M, Mahieux R, Kfoury Y, Abdulhay M, Yazbeck V, Hermine O, de The H, Pique C, Bazarbachi A. Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation. Blood. 2006 May 15;107(10):4021-9.

Heraud JM, Mortreux F, Merien F, Contamin H, Mahieux R, Pouliquen JF, Wattel E, Gessain A, de The H, Bazarbachi A, Hermine O, Kazanji M. The efficacy of combined therapy of arsenic trioxide and alpha interferon in human T-cell leukemia virus type-1-infected squirrel monkeys (Saimiri sciureus). Antiviral Res. 2006 Jul;70(3):132-9.

Lallemand-Breitenbach V, de The H. CK2 and PML: regulating the regulator. Cell. 2006 Jul 28;126(2):244-5.

Condemine W, Takahashi Y, Zhu J, Puvion-Dutilleul F, Guegan S, Janin A, de The H.
Characterization of endogenous human promyelocytic leukemia isoforms. Cancer Res. 2006 Jun 15;66(12):6192-8.

Zhou J, Peres L, Honore N, Nasr R, Zhu J, de The H. Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization. Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9238-43.

Publié le jeudi 03 mai 2007