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Cell death and drug resistance in lymphoproliferative disorders

A key goal in cancer research is the development of new therapeutic agents with the capacity to overcome the drug resistance resulting from programmed cell death (PCD) blockage. It is therefore of the highest interest to find original approaches that can overcome PCD refractoriness.
With this aim, our research team is devoted to characterize the molecular mechanisms regulating cell death in tumor cells, with a special interest in the modulation of PCD in chronic lymphocytic leukemia (CLL), the most common haematological malignancy in Western countries. CLL is characterized by an accumulation of monoclonal B cells (CD20 , CD5 , and CD23 ) in the peripheral blood, bone marrow, and secondary lymphoid organs that leads to the progressive failure of the immune and hematopoietic systems. Despite intense research and pharmaceutical development, CLL remains an incurable disease. Indeed, 15-25% of patients remain or become refractory to the current chemotherapeutic regimes. Moreover, patients with a dysfunctional TP53 gene (~7%) require a specific aggressive therapy that often yields negative results. In the forthcoming period (2014-2018), we plan to further advance our knowledge of the caspase-independent mode of PCD and to enlarge our focus of interest on the relationship existing between cell death blockage and drug resistance in B-cell lymphoproliferative disorders. Four ongoing projects will be pursued in future years: 

 

1. Drug resistance in B-lymphoproliferative disorders. We will pursue the characterization of the biology of chronic lymphoproliferative disorders and their possible consequences on therapeutic strategy. We will focus on the:

- Identification and characterization of chromosomal abnormalities associated to drug resistance, poor prognosis, and inhibition of programmed cell death (PCD) in B-cell malignancies.
- Molecular analysis of CLL selected for the aggressive course of disease and/or drug resistance (e.g., with dysfunctional TP53).
- Functional assessment of the cell survival and drug resistance associated with B-cell receptor.

2.  CD47-mediated cell death in chronic lymphocytic leukemia. As indicated above, drug resistance remains a major cause of treatment failure in CLL and its inevitable fate due to the prolonged natural course of disease and the repeated treatments. Most of these treatments induced cytotoxicity in CLL cells via a caspase-dependent mechanism with a quite variable outcome. Indeed, as leukemic B cells present molecular defects that make them particularly resistant to the caspase-dependent PCD pathway, a significant group of CLL patients are refractory to these chemotherapeutics. For that reason, the introduction of new drugs that induce PCD via caspase-independent PCD pathways could open the way to novel therapeutic strategies in CLL treatment. From this perspective, we will seek the development of new caspase-independent PCD therapeutic approaches. In particular, we are presently focused on the development and functional validation of a peptide-based therapeutic. This therapeutic is designed to specifically eliminate malignant CD5 CLL cells, including those from high-risk individuals (and not the residual CD5- B-cells or the T-cells of the CLL patient), by induction of CD47-mediated caspase-independent PCD. This study includes the analysis of B-lymphocytes with dysfunction in ATM and TP53 genes (cells obtained from patients presenting a characteristic drug resistance).

Figure Legend. (a) Blood smears from Chronic Lymphocytic Leukemia (CLL) patients (May-Grünwald-Giemsa staining). (b) Schematic model for CD47-mediated death in CLL cells. (c) Theoretical model of the H2AX/AIF/CypA complex observed in MNNG-treated cells. (d) Oxygen consumption rates (OCR) of Control and AIF KO cells determined by oxymetry using a Clark’s electrode


3. Caspase-independent cell death as a means to overcome drug resistance in tumor cells. As a continuation of the work developed by Dr. Susin’s team since 2002, a part of our team is devoted to performing an exhaustive characterization of both the principal agents involved and the molecular pathways implicated in caspase-independent cell death. We think that the understanding of caspase-independent mechanisms in normal and pathological regulation of PCD may provide new options to kill tumor cells (our long term goal). Indeed, targeting only the caspase-dependent PCD pathway often does not provide a sufficient (or efficient) approach to the treatment of diseases resulting from the deregulated proliferation versus death equilibrium (e.g., CLL, see above). In this way, Apoptosis Inducing Factor (AIF) was identified by exploring apoptotic processes in mitochondria/nuclei cell free systems. Since this discovery, the study performed by Dr. Susin’s team has revealed some of the molecular mechanisms used by this mitochondrial protein to be released from mitochondria and to induce caspase-independent cell death. Now, we plan to extend the assessment of the mechanisms regulating AIF-mediated PCD and to analyze the relationship between the mitochondrial (OXPHOS) and nuclear activities of AIF..

4. Finally, we are interested in linking the mitochondrial metabolism to the normal or aberrant cell development. Mitochondrial energy metabolism is crucial for providing the cell with the fuel it needs to perform a host of biological processes, and defects in this pathway can have serious consequences for cell development and many disease states, including hematological cancer. Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Previous studies have demonstrated that the loss of AIF provoked a failure in the oxidative phosphorylation capacity of the cell. Through the analysis of different AIF KO mouse models (e.g., hematopoietic lineage-specific deletion), this part of our research program plan to assess the relevance of a functional oxidative phosphorylation system (or a functional mitochondrial metabolism) in the normal or tumoral cell development.

Team Leader:  Santos A. SUSIN (Dr)

Team Members: Brigitte BAUVOIS (Dr), Elise CHAPIRO (Dr), Myrto COSTOPOULOS (Dr), Frédéric DAVI (Pr), Magali LE GARFF-TAVERNIER (Dr), Hélène MERLE-BERAL (Pr), Florence NGUYEN-KHAC (Pr).
Sylvie BAUDET (Tech, GH Pitié-Salpétrière), Sandrine BOUCHET (Eng), Myriam BOUDJOGHRA (Tech, GH Pitié-Salpétrière), Marie-Noëlle BRUNELLE-NAVAS (Eng), Clémentine GABILLAUD (Tech, GH Pitié-Salpétrière), Linda HERBI (Eng), Christine MUAMBA (Tech).
Audrey BERTAUX (PhD), Nadia BOUGACHA (PhD), Elodie PRAMIL (PhD).

Administration:
  Véronique BARRAUD  

Contact details : tel: 33 1 44 27 81 93 / 33 1 44 27 90 38  
Fax: 33 1 44 27 90 36
Email: veronique.barraud@crc.jussieu.fr

Web site: http://susinlab.com

 

Selected Publications

  • Martinez-Torres AC, Quiney C, Attout T, Boullet H, Herbi L, Vela L, Barbier S, Chateau D, Chapiro E, Nguyen-Khac F, Davi F, Le Garff-Tavernier M, Moumné R, Sarfati M, Karoyan P, Merle-Béral H, Launay P, Susin SA. 2015. CD47 agonist peptides induce programmed cell death in refractory chronic lymphocytic leukemia B cells via PLCγ1 activation: evidence from mice and humans. PLoS Medicine, 12(3):e1001796
  • Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, Diop M, Scourzic L, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kikushige Y, Davi F, Lambert J, Gautheret D, Merle-Beral H, Sutton L, Dessen P, Solary E, Akashi K, Vainchenker W, Mercher T, Droin N, Ogawa S, Nguyen-Khac F*, Bernard OA*. 2014. Acquired initiating mutations in early hematopoietic cells of CLL patients. Cancer Discovery, 4(9):1088-101. * Senior co-authorship.
  • Cabon L, Galan-Malo P, Bouharrour A, Delavallée L, Brunelle-Navas MN, Lorenzo HK, Gross A, and Susin SA. 2012. BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation. Cell Death and Differentiation, vol 19, pp. 245-256.
  • Baritaud M, Cabon L, Delavallée L, Galán-Malo P, Gilles ME, Brunelle-Navas MN, Susin SA. 2012. AIF-mediated caspase-independent necroptosis requires ATM and DNA-PK-induced histone H2AX Ser139 phosphorylation. Cell Death and Disease, 3:e390.
  • Artus C, Boujrad H, Bouharrour A, Brunelle MN, Hoos S, Yuste VJ, Lenormand P, Rousselle JC, Namane A, England P, Lorenzo HK, and Susin SA. 2010. AIF promotes chromatinolysis and caspase-independent programmed necrosis by interacting with histone H2AX. EMBO Journal, vol 29, pp. 1585-1599.
  • Chapiro E, Russell LJ, Struski S, Cave H, Radford-Weiss I, Valle VD, Lachenaud J, Brousset P, Bernard OA, Harrison CJ, Nguyen-Khac F. 2010. A new recurrent translocation t(11;14)(q24;q32) involving IGH@ and miR-125b-1 in B-cell progenitor acute lymphoblastic leukemia. Leukemia, vol. 24, pp. 1362-1364.
  • Merle-Béral H, Barbier S, Roué G, Bras M, Sarfati M, and Susin SA. 2009. Caspase-independent type III PCD: a new means to modulate cell death in chronic lymphocytic leukemia cells. Leukemia, vol. 23, pp. 974-977.

 

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