Faculté de médecine Sorbonne Université - Site Saint-Antoine - 10e et 11e étages - 27, rue Chaligny, 75012 Paris, France
Projet CONECT-AML : https://www.conect-aml.fr/
The team “Haematopoietic and Leukemic development: diseases and cell therapy” is led by François Delhommeau, professor of haematology. It comprises of 11 researchers or faculty members (9 HDR), 5 engineers and technical staff, and annually greets 2 to 4 postdocs and PhD students, 3 to 6 second-year master and 1 to 3 first-year master. Our works focus on two fundamental aspects of haematology: the comprehension of the mechanisms which lead to acute myeloid leukaemia (AML) and the study of normal haematopoiesis, especially erythropoiesis, in order to develop cell therapies. Our team is divided into three groups working on these topics with close interactions.
The first group, “AML genetics”, led by Hélène Lapillonne and François Delhommeau, studies the genetic lesions that lead to leukemic development both in children and adults. We aim to decipher the clonal architecture of AML, especially AML secondary to predisposition syndromes such as Shwachman-Diamond syndrome or GATA2 syndrome. We also focus on AML with TP53 mutations and secondary to myeloproliferative neoplasms.
The second group, “stroma and stem cells" led by Pierre Hirsch, focuses on the link between the bone marrow microenvironment, the development of clonal haematopoiesis and AML. These works aim to understand the dialogue between mesenchymal stem cells and preleukemic/leukemic stem cells, to assess the composition of normal and pathological bone marrow plasma, and to investigate the specific role of some cytokines and haematopoietic growth factors in AML development.
The third group, “sources of blood and erythropoiesis”, led by Yaël Zermati and Laurence Guyonneau-Harmand, is dedicated to the study of physiological and pathological erythropoiesis, to the ex-vivo production of erythrocytes and to the generation of functional haematopoietic stem cells from induced pluripotent stem cells. These two topics are supported by the French National Blood Service (The Etablissement Français du Sang).
The team tightly works with the clinical and biological wards of Saint-Antoine and Trousseau teaching hospitals, but also with the French national registry of congenital neutropenia led by Jean Donadieu. Through research programs, we collaborate tightly with other teams. Our most active collaborations are with Thierry Jaffredo’s team from the Institute of biology Paris-Seine, with Olivier Hérault’s team from Tours teaching hospital and with Hana Raslova’s team from Gustave Roussy Institute.
The “AML genetics” group deciphered the clonal architecture of acute myeloid leukaemia (AML)(Hirsch et al, Nature Communications, 2016). This work has led to several projects. First, the team has been developing tools to use the clonal composition as a patient-specific marker to monitor the minimal residual disease in AML (Hirsch et al, Haematologica, 2017). The second project investigates the unusual way of development of TP53-mutated AMLs that do not follow a chemo- or radiotherapy for a first cancer. These AMLs can occur "de novo" or in the context of a myelodysplastic syndrome, a myeloproliferative syndrome, or a predisposition syndrome in young patients, with specific selection of founding TP53-mutant clones (Hirsch et al, Nature Communications, 2016 ; Donadieu et al, Blood 2017, Donadieu & Delhommeau, Blood 2018). Finally, the group is also working towards making the connection between clonal composition and the crosstalk between leukemic cells and their stroma.
The “sources of blood and erythropoiesis” group developed an original procedure of IPS differentiation to generate a cell population able to repopulate with human hematopoiesis the bone marrow of xenografted immune-compromised mice (Harmand et al, submitted). Likewise, in direct line with the historical works of the team (Giarratana et al, Blood 2011), the group develops tools to improve both the cell source and the medium to reach the high-scale production of erythrocytes in culture. The team relies on the arrival of Yael Zermati who established a proteomic reference database of the erythroid differentiation (Gautier EF, Zermati Y et al, Cell Reports 2016).