NOVAMOLE

Novel somatic mutations in ABCA1 in chronic myelomonocytic leukaemia

Coordinatore	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)    more  Organization address address: 101 Rue de Tolbiac city: PARIS postcode: 75654 contact info Titolo: Mrs. Nome: Veronique Cognome: Legros Email: send email Telefono: 33491827015 Fax: 33491827048
Nazionalità Coordinatore	France [FR]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-06-01   -   2018-05-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)  Organization address address: 101 Rue de Tolbiac city: PARIS postcode: 75654 contact info Titolo: Mrs. Nome: Veronique Cognome: Legros Email: send email Telefono: 33491827015 Fax: 33491827048	FR (PARIS)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'Background: Altered high-density lipoprotein (HDL)-cholesterol homeostasis has been observed in hematologic malignancies but genetic evidences proving causality have been lacking. The ability of HDL to promote cholesterol efflux depends on two ATP-binding cassette transporters ABCA1 and ABCG1, which exhibit anti-myeloproliferative activity in preclinical mouse models. Hypothesis: Somatic mutations in ABCA1 and ABCG1 may be observed in myeloproliferative disorders and could be functionally inactive disabling both cholesterol efflux and anti-tumor activity. Preliminary data: Five new somatic mutations in ABCA1 were identified out of 26 tumor samples from patients with chronic myelomonocytic leukaemia (CMML) with an unexpected frequency of 19% and conferred a proliferative advantage when transfected into HEK293 cells. Aims: The aim of this study is to 1) test the functional relevance of newly identified ABCA1 mutants on myeloproliferative diseases and 2) apprehend the molecular mechanisms that could provide a proliferative advantage to these mutants. Methods: We will take advantage of the generation of these mutants to test their relevance (Aim. 1) and mechanisms of action (Aim. 2) both in vitro in relevant myeloblast cell lines and in vivo by performing a transplantation of bone marrow cells transduced with these mutants.

Keywords: Leukaemia, HDL cholesterol, ATP-binding cassette transporters, human somatic mutations'