Project GERMPN (Study of familial myeloproliferative neoplasms : search for genetic abnormalities...) | ANR - Agence Nationale de la Recherche ANR funded project | ANR - Agence Nationale de la Recherche

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ANR funded project

JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique (JCJC SVSE 1) 2013
Projet GERMPN

Study of familial myeloproliferative neoplasms : search for genetic abnormalities and their functions.

Myeloproliferative neoplasms (MPN) are clonal malignancies caused by genetic defects that occur in the hematopoietic stem cell and result in overproduction of one or several myeloid lineages (i.e. erythoid, megakaryocytic and granulocytic). The MPN are classified into three broad categories: 1) chronic myeloid leukemia, 2) classical MPN including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) and finally 3) unclassified MPN. The laboratory focuses on the "classical" BCR-ABL-negative MPN and has played a crucial role in identifying, a recurrent mutation in the JAK2 gene called JAK2V617F that leads to constitutive activation of the kinase in half of PMF and ET and in 95% of PV. However in about 40% of ET and PMF the driver molecular event(s) is currently unknown.
There is epidemiological evidence that familial forms are frequent in MPN. Familial cases are usually subdivided in two overlapping entities: a first group gathering inherited disorders and a second considered as MPN-like disorders with hereditary predisposition. 1) The first entity is not a MPN, but rather a familial erythrocytosis, neutrophilia or thrombocytosis with an autosomal dominant pattern and an early appearance (complete penetrance) of the hematological abnormalities. They are considered as non-malignant diseases due to the polyclonal nature of hematopoiesis. Nevertheless, they are due to germline mutations of genes also mutated in sporadic cases of MPN, but often on different codons. Therefore, it is critical to study these entities for a global understanding of MPN. 2) The second entity is a true predisposition to MPN. Disease occurs in adulthood and is usually transmitted by autosomal inheritance with incomplete penetrance. These familial cases are indistinguishable from the sporadic cases that are associated with acquired genetic abnormalities. Indeed, acquired mutations in signaling molecules such as JAK2V617F mutation or in epigenetic regulators like TET2 can be detected when the MPN has developed, but not before. To the best of our knowledge, no major MPN predisposing gene has been identified yet, and data linkage analysis suggest a large genetic heterogeneity.
The project will be divided into four tasks: i) Characterize the function of novel JAK2 mutations found in two families with a type 1 autosomal dominant thrombocytosis with complete penetrance; ii) Characterize the gene(s) involved in the predisposition to ET rapidly evolving to acute myeloid leukemia (AML) in two MPN families with an autosomal dominant inheritance; iii) Study the role of four EPOR variants found in five families with autosomal dominant MPN; iv) identify the predisposing genes involved in other large families.
All these aims are based on strong genetic preliminary data and our overall objective is to model the predisposing genes to address their function in hematopoiesis in a comprehensive series of studies. Since they are germline mutations, we intend to use both classical approaches including cell lines and mouse models, but also original technologies such as induced pluripotent cells (iPS). More precisely, the iPS technology will allow to focus on the role of these predispositions during ontogeny.
In this context it is very important to identify these genes since their discovery will be a major advance in understanding not only the mechanisms of predisposition but also of oncogenesis. In other disorders predisposed to evolve as malignant diseases, the identified susceptibility gene was always shown to be involved in a major biological process (development, DNA repair, checkpoint, etc…). In addition, it is not excluded that these MPN-predisposing genes will also be involved in the pathogenesis of sporadic cases probably as initiating events.

Partners

IGR U 1009 INSTITUT GUSTAVE ROUSSY

INSERM UMR1009 Institut National de la Santé et recherche médicale - laboratoire d'hématopoïèse normale et pathologique

ANR grant: 380 826 euros
Beginning and duration: octobre 2013 - 36 mois

 

ANR Programme: JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique (JCJC SVSE 1) 2013

Project ID: ANR-13-JSV1-0007

Project coordinator:
Madame Isabelle PLO (INSTITUT GUSTAVE ROUSSY)

 

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The project coordinator is the author of this abstract and is therefore responsible for the content of the summary. The ANR disclaims all responsibility in connection with its content.