PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Blood Année : 2021

PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL

Charlotte Smith

Résumé

T-cell acute lymphoblastic leukemia (T-ALL) is a group of aggressive hematological cancers with dismal outcomes that are in need of new therapeutic options. Polycomb repressor complex 2 (PRC2) loss-of-function alterations were reported in pediatric T-ALL, yet their clinical relevance and functional consequences remain elusive. Here, we extensively analyzed PRC2 alterations in a large series of 218 adult T-ALL patients. We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to early thymic precursor ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients respond poorly to prednisone and have low bone marrow blast clearance and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with bromodomain and extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data have uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.
Fichier principal
Vignette du fichier
PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL_revised.pdf (229.72 Ko) Télécharger le fichier

Dates et versions

hal-03513058 , version 1 (11-02-2022)

Identifiants

Citer

Guillaume Andrieu, Milena Kohn, Mathieu Simonin, Charlotte Smith, Agata Cieslak, et al.. PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL. Blood, 2021, 138 (19), pp.1855-1869. ⟨10.1182/blood.2020010081⟩. ⟨hal-03513058⟩
18 Consultations
125 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More