Innovating Works

PML-THERAPY

Financiado
HARNESSING PML NUCLEAR BODIES FOR LEUKAEMIA THERAPY
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... 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 ver más
30/06/2024
INSERM
3M€
Duración del proyecto: 70 meses Fecha Inicio: 2018-08-06
Fecha Fin: 2024-06-30

Línea de financiación: concedida

El organismo H2020 notifico la concesión del proyecto el día 2024-06-30
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2017-ADG: ERC Advanced Grant
Cerrada hace 7 años
Presupuesto El presupuesto total del proyecto asciende a 3M€
Líder del proyecto
INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5