Team: Molecular Mechanisms of Chronic Inflammation in Hematological Diseases
The research theme of the team is the elucidation of molecular mechanisms (chronic infection or hypoxia, genetic alterations) that cause inflammation and may lead to chronic hematological malignancy (models of myeloproliferative neoplasms, myeloma and erythrocytoses).
Genomics Research for hereditary Erythrocytosis and related Diseases (GenRED).
The GenRED project aims to identify germline mutations that cause hereditary erythrocytoses (HE), rare haematological diseases characterized by excessive production of red blood cells. HE should be dstinguished from Polycythemia Vera, a myeloproliferative neoplasm characterized by the presence of acquired JAK2-V617F mutation. HE can be either inherited or de novo, diagnosed in adult patients with no family history. In addition, other cases of erythrocytosis discovered in adults and without known cause are called idiopathic erythrocytosis (IE). HE may be complicated by severe thrombo-embolic or haemorrhagic events, pulmonary arterial hypertension and, in some cases, tumours (pheochromocytoma, paraganglioma). The 8 genes identified so far as causing HE lie at the crossroads of major biological pathways (oxygen sensing, metabolism, inflammation) and are implicated in multiple diseases. However, in 80% of HE/IE cases the cause remains unknown meaning that no proper diagnosis can be made, no prognosis or advice can be provided to HE/IE patients and their families, and no curative treatment exists.
The GenRED project is based on multiple expertises located in different centers:
– Medical expertise: S. Hermouet and F. Girodon (CHU Dijon) coordinate of the recruitment and the diagnostic work-up of patients.
– Genetic expertise: S. Bézieau (Head of the Genetic Department, CHU Nantes) organizes the molecular diagnosis of erythrocytoses. The characterization of the genetic and molecular bases of HE and IE is performed by Next Generation Sequencing. The panel of tested genes contains genes already described in association with HE and candidate genes (in which mutations have already been identified in at least one family by Team 16). If a mutation is identified, a medical diagnosis is made and sent to the physicians of patients, who can then benefit from appropriate genetic counselling (screening of relatives, appropriate follow-up and treatment).
– Genomic expertise: R. Redon (Head of the genomics and bioinformatics core facility of Nantes (IBiSA)) is in charge of whole exome sequencing in patients and relatives with familial history of erythrocytosis and no mutation identified.
– Scientific expertise of the oxygen sensing pathway: B. Gardie coordinates the validation of the clinical relevance of new mutations and genes found in HE/IE patients using in cellulo and in vitro functional studies. These functional studies plan to identify precise molecular mechanisms involved in HE and factors responsible for the severity and complications of the disease.
The aim of the GenRED project is to allow appropriate diagnosis and the identification of new molecular pathways involved in the regulation of human erythropoiesis.