PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL.
(2021) Blood — Vol. 138, n° 19, p. 1855-1869 (2021)
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Andrieu, Guillaume P 
Smith, Charlotte
- Abstract
- T-cell acute lymphoblastic leukemia (T-ALL) are aggressive hematological cancers with dismal outcomes, and 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 ETP-ALL. PRC2 loss of function associates with activating mutations of the IL7R/JAK/STAT pathway. PRC2-altered T-ALL patients poorly respond to prednisone, 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 has uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.
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Citations
Andrieu, G. P., Kohn, M., Simonin, M., Smith, C., Cieslak, A., Dourthe, M.-E., Charbonnier, G., Graux, C., Rigal-Huguet, F., Lheritier, V., Dombret, H., Spicuglia, S., Rousselot, P., Boissel, N., & Asnafi, V. (2021). PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL. Blood, 138(19), 1855-1869. https://doi.org/10.1182/blood.2020010081 (Original work published 2021)