Community Research and Development Information Service - CORDIS

Final Report Summary - NOVAMOLE (Novel somatic mutations in ABCA1 in chronic myelomonocytic leukaemia)

• State-of-the art
Hematologic malignancies such as leukemia are diagnosed in about 250,000 patients worldwide. Despite current available treatment, additional therapeutic approaches are needed to face the different etiology of myeloproliferative neoplasms. A decrease in plasma high-density lipoprotein (HDL)-cholesterol levels has been observed in hematologic malignancies, especially chronic myelomonocytic leukaemia (CMML), but genetic evidences proving causality in humans have been lacking. The ability of HDL to remove the excess of cholesterol from intracellular pools depends on ATP-binding cassette transporters such as ABCA1, which exhibit anti-myeloproliferative activity in preclinical mouse models.
• Scientific progress and results
We have identified 5 novel somatic mutations in ABCA1 out of 26 tumor samples from patients with chronic myelomonocytic leukaemia (CMML) with an unexpected frequency of 19%. We have generated myeloblast-like cell lines expressing mutant ABCA1 and found that these mutations confer a proliferative advantage in vitro by disrupting cellular cholesterol efflux and altering intracellular cholesterol homeostasis (Aim 1). Additionally, in vivo work in preclinical models of leukemia revealeded that transplantation of mutant ABCA1 bone marrow accelerated myloproliferative disorders (Aim 1). Mechanistically, we identified that ABCA1 mutations acted at the level of hematopoietic stem cells to increase growth hormone signaling, an effect completely dependent on cholesterol accumulation (Aim2). Altogether these findings prove the causality between defective cholesterol efflux pathway (i.e, oncogenic ABCA1 mutations) and chronic myelomonocytic leukaemia (CMML) in humans. Therapeutics aimed at raising cholesterol efflux pathways may ultimately provide novel strategy for the treatment of CMML disease.
• Prospects of the research career development and re-integration
The CIG grant allowed me to successfully support the progress of this project, which has been led in part by a PhD student, Manon Viaud. She was recruited thanks to a regional Inserm/PACA fellowship and this wouldn’t have been possible without the generation of preliminary data through the CIG support. Since this, our group has grown and we now receive additional funding.
From a career perspective, after starting my ATIP-AVENIR group, I received the EAS young investigator award in 2013 and the Daniel Sterinberg Early Career Investigator award from the AHA in 2015. I have been recruited in 2015 on a permanent position within Inserm as a Director of Research. I have been given faculty and institutional responsibilities including evaluation of several commissions of trust, external referee for PhD students and habilitation thesis and more recently I joined the board of the NSFA (French atherosclerosis society). Finally, in 2018, I was the recipient of a prestigious ERC-consolidator grant. In addition to research and faculty responsibilities, I have been largely communicating on the research of my group to enhance our project’s visibility not only in term of scientific publications (h-index: 34) but also in term of national and international meetings (over 30 meetings including 5 related to the present topic) and several outreach activities to exchange and communicate with the public.

Reported by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE (INSERM)
France

Subjects

Life Sciences
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