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PML-THERAPY SIGNED

HARNESSING PML NUCLEAR BODIES FOR LEUKAEMIA THERAPY

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EC-Contrib. €

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Partnership

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 PML-THERAPY project word cloud

Explore the words cloud of the PML-THERAPY project. It provides you a very rough idea of what is the project "PML-THERAPY" about.

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Project "PML-THERAPY" data sheet

The following table provides information about the project.

Coordinator
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE 

Organization address
address: RUE DE TOLBIAC 101
city: PARIS
postcode: 75654
website: www.inserm.fr

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country France [FR]
 Total cost 2˙500˙000 €
 EC max contribution 2˙500˙000 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2017-ADG
 Funding Scheme ERC-ADG
 Starting year 2019
 Duration (year-month-day) from 2019-04-01   to  2024-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE FR (PARIS) coordinator 2˙400˙000.00
2    American University of Beirut LB (BEIRUT) participant 100˙000.00

Map

 Project objective

In acute promyelocytic leukaemia (APL), retinoic acid (RA) and Arsenic trioxide (As) bind PML/RARA and promote its degradation. Exploring the mechanistic bases for APL response to the RA/As combination, we found that upon PML/RARA degradation the normal PML allele activates a PML/P53 checkpoint absolutely required for APL cure in mice or patients. Physiologically, PML behaves as an oxidative stress sensor and contributes to redox homeostasis. PML organizes nuclear bodies (NBs), domains that recruit multiple client proteins and may facilitate their post-translational modifications (PTM), particularly conjugation of SUMOs. This somehow controls multiple downstream pathways such as P53, but also RB, HIF1A or interferon (IFN). In APL, NB-disruption blunts P53-driven senescence, contributing to oncogenesis and therapy resistance. Critically, PML expression and/or NB-formation are lost upon many viral infections or during cancer development. The mechanism(s) underlying the selective pressure to loose PML expression in multiple cancers remains incompletely understood. Our aim is to mechanistically dissect PML signalling in vivo and therapeutically restore it in malignancies where it is inactivated. We first propose a broad exploration of PML in mice to identify basal and stress-induced PML PTM and identify the repertoire of proteins sumoylated in a PML- dependent manner. We will generate a series of PML knock-in mutant mice and analyse their P53- regulated redox homeostasis. We will mechanistically explore PML/P53-driven senescence in three leukaemia models where we have evidence for basal or therapy-responsive NB-modulation: acute myeloid leukaemia expressing NPMc and IFN-sensitive Tax- or JAK2-driven leukaemias. We will screen chemical libraries for drugs modulating PML expression and/or NB biogenesis. Finally, we will integrate our findings to elaborate innovative therapeutic strategies based on restoration of the PML/P53 checkpoint in leukaemia with unmet medical needs

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