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HARNESSING PML NUCLEAR BODIES FOR LEUKAEMIA THERAPY

HARNESSING PML NUCLEAR BODIES FOR LEUKAEMIA THERAPY

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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Host institution

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

Address

Rue De Tolbiac 101
75654 Paris

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 2 500 000

Beneficiaries (1)

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INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France

EU Contribution

€ 2 500 000

Project information

Grant agreement ID: 785917

Status

Ongoing project

  • Start date

    1 September 2018

  • End date

    31 August 2023

Funded under:

H2020-EU.1.1.

  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

Hosted by:

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE

France