Team: Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications
Physiopathology and treatment of hematological disorders
The Hematology Department at Necker Children’s Hospital covers several aspects of the physiopathology and treatment of malignant and benign hematologic disorders, including adult patients with primary and secondary immunodeficiencies and mastocytosis. It works in close collaboration with the Necker pathology, biology, cytogenetics, molecular biology, biotherapy, infectious disease, transplantation and pediatric immune hematology departments. Our group aims at defining new therapeutic strategies for hematologic disorders, on the basis on in vitro and in vivo studies of rare diseases.
Erythropoiesis regulation and its clinical applications
We were the first group to demonstrate that while caspase activation is known to be important for the apoptosis of erythroid cells, it is also critical for erythroid differentiation. In this field, the current projects are (i) deciphering the mechanisms of caspase activation and identifying caspase targets and parameters that control caspase activity and the availability of their targets during differentiation, (ii) characterizing the involvement of caspases in the physiopathology of erythroid disorders such as thalassemia, myelodysplastic syndrome and congenital erythroblastopenia, (iii) determining the potential therapeutic application of caspases triggering in erythropoiesis disorders. By studying iron metabolism in erythroid cells, we have shown that the transferrin receptor (TfR) activation induces cell signaling. This finding led to the demonstration that TfR could be a target for treatment of cancer cells that express high levels of this receptor by inducing the apoptosis and differentiation of leukemic cells, for example. In collaboration with the biotech company Inatherys, we are currently developing an antibody directed against TfR receptor, with a view to treating malignant diseases.
Our recent findings revealed that unexpectedly 5-HT is of pivotal importance to ensure normal erythropoiesis and red blood cell (RBC) survival in mice Tph1−/− mice display morphological and cellular features of ineffective erythropoiesis that we will explore. We will test whether serotonylation of proteins, interactions with cognate receptors that are expressed in erythroblasts, or modulation of the modulation of ROS/TGF-β axis are involved in preventing ineffective erythropoiesis. We will investigate whether 5-HT expression plays a role in erythroid disorders including thalassemia, MDS and primary myelofibrosis (MF) since our preliminary data suggest that old Tph1−/− mice develop MF.Our data indicate that Tph1−/− RBCs are damaged or abnormal since they are more sensitive to phagocytosis in vitro and have a reduced circulating half-life in vivo. Our preliminary results suggest that addition of 5-HT to mouse and human RBCs in vitro, extends their shelf live. Mechanisms involved will be studied and hopefully will lead to new concepts and techniques regarding RBCs production/survival.
Some epidemiological studies and experimental evidences suggest that old red blood cells transfused may be detrimental. We will investigate epidemiologically in patient’s cohort the role of transfusion in outcome of hematological malignancies (Leukemia, Multiple myeloma, Lymphoma) and in mice models we will try to assess the impact of new and old red blood cells treated or not by 5-HT or derivative compounds in the development of tumors and or in the control of autoimmune diseases and mechanisms involved.