Published on 02.02.2021
Research Acceleration
Olivier Hermine: genetics and hematology
Olivier Hermine's research team specializes in hematological diseases such as mastocytoses, which are caused by the accumulation of a type of blood cell, mast cells, in various tissues and can lead to malignant forms, but also to other blood cancers. The common point of this research is the study of the production mechanisms of the different blood cells. The slightest failure in this system can lead to the production of a pathological cell.
Understanding this system at the molecular and cellular level sheds light on the mechanisms of anemia, a disease that is accompanied by a drop in the number of red blood cells, but also on other pathologies such as cancers, where the cells proliferate too much, and so-called degenerative diseases, where the cells die early, explained Olivier Hermine, who explored all of these fields during his induction at the Academy of Sciences. In particular, his team is working to identify the signaling pathways involved in the development of mast cell leukemia. He has thus participated in identifying the mutation at the origin of mastocytosis that promotes the "cancerization" of cells. This mutation affects the C-kit gene, an oncogene, which regulates cell division. He demonstrated that C-kit mutations do not affect the protein in the same way in children and adults, and uncovered a molecule that can block these mechanisms: masitinib. The start-up AB Science, of which he is scientific advisor, is in charge of the development of this molecule and the study of its efficacy in various cancers and other pathologies.
Now, with his team, with the aim of treating patients with proliferative diseases such as leukemia, but also other cancers that also need iron to proliferate and survive, he is developing an antibody to treat certain aggressive tumors, those that proliferate the most being those that express the most receptors and therefore theoretically the most sensitive to treatment.
Sylvain Latour : From immune deficiencies and cancers associated with Epstein Barr virus infection to the development of new therapeutic approaches for cancer
Sylvain Latour's team is studying the mechanisms of the immune response involved in the control of infection by the Epstein Barr Virus (EBV) which is the main human virus responsible for several cancers including certain types of lymphomas and carcinomas. Its study models are genetic immunodeficiencies leading to a particular susceptibility to EBV infection leading to the development of lymphoproliferative and inflammatory diseases such as lymphoma and hemophagocytic lymphohistiocytosis. The team recently showed that CTPS1 (CTP synthetase 1), an enzyme involved in the de novo synthesis of the CTP nucleotide, is a key factor in the proliferation of activated lymphocytes. CTPS1 deficiency in humans leads to a high susceptibility to viral infections, in particular EBV infection, highlighting the crucial role of proliferation and expansion of activated T lymphocytes during immune responses.
Based on this discovery, Step-Pharma (www.step-ph.com) was created (of which Alain Fischer and Sylvain Latour are the creators and scientific collaborators) to develop CTPS1 inhibitors that could represent a new treatment for diseases caused by excessive T cell proliferation, such as T lymphoma. Other work by the team has also led to the proposal of a new gene therapy aimed at re-initiating an anti-tumor immune response for the treatment of certain B lymphomas deficient in the CD70 molecule. The proof of concept of this approach is currently being studied.
Jean-Pierre de Villartay and Patrick Revy: from DNA repair defects to cancers
The team of Jean-Pierre de Villartay and Patrick Revy is interested in the repair of lesions occurring in genetic material. Knowing that the failure of DNA repair is one of the mechanisms involved in cancers, their research has obvious repercussions in cancerology. The team is working to understand the consequences of DNA repair defects in human pathologies, linked in particular to the immuno-hematological system, but also to certain rare childhood cancers. In the team, Erika Brunet studies in particular the mechanisms of genomic instability and models rare pediatric lymphomas and sarcomas, such as Ewing's tumors, by CRISPR/Cas9.
Nadine Cerf-Bensussan: when celiac disease turns into invasive lymphoma.
Celiac disease has been at the heart of Nadine Cerf-Bensussan's research for many years, and for good reason. This Inserm research director, in charge of a laboratory at Imagine, is a specialist in the links between the immune system and the intestine. When the cooperation between the cells lining the intestinal wall and those of the immune system deteriorates, the risk of inflammation or any other damage is great, as illustrated by celiac disease. In approximately 0.5% of these patients, intestinal damage does not heal despite a strictly adhered to gluten-free diet indicating the development of refractory celiac disease. The work carried out by the Nadine Cerf-Bensussan team, in close collaboration with the CELAC network, has contributed to the elucidation of resistance mechanisms in refractory celiac disease. In half of the patients, resistance to the diet reveals a lymphoma that first evolves at low noise and then can develop into an invasive lymphoma with a very poor prognosis.
Jeanne Amiel and Stanislas Lyonnet: when the same genes are associated with cancers or congenital malformations depending on the nature of their mutation.
The team of Pr Jeanne Amiel and Stanislas Lyonnet has been studying for about ten years the case of children suffering from undiagnosed multiple malformations affecting the nervous system of the digestive tract, the development of the brain, the heart and the skeleton. This has been the case in the emblematic examples of the RET and PHOX2B genes. But very recently, in 2020, this laboratory, in collaboration with several international teams, demonstrated that the loss of function of a receptor of the Sonic Hedgehog pathway, encoded by the SMO gene, is responsible for the congenital malformations of these children. However, somatic mutations of the same SMO gene have been reported in a variety of tumors.
This discovery shows that genes involved in adult cancers through somatic mutations in tissues may, in children, through other mutations and other mechanisms, be involved in congenital malformations, and that an oncogene, involved in tumor predisposition mechanisms in adulthood, may, in the case of other mutations that inactivate this gene, be responsible for birth defects.