Fiche publication
Date publication
décembre 2022
Journal
Blood cancer discovery
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FEUGIER Pierre
,
Pr BROSEUS Julien
Tous les auteurs :
Ten Hacken E, Sewastianik T, Yin S, Brunsting Hoffmann G, Gruber M, Clement K, Penter L, Redd RA, Ruthen N, Hergalant S, Sholokhova A, Fell G, Parry EM, Broseus J, Guieze R, Lucas F, Hernandez-Sanchez M, Baranowski K, Southard J, Joyal H, Billington L, Regis FFD, Witten E, Uduman M, Knisbacher BA, Li S, Lyu H, Vaisitti T, Deaglio S, Inghirami G, Feugier P, Stilgenbauer S, Tausch E, Davids MS, Getz G, Livak KJ, Bozic I, Neuberg DS, Carrasco RD, Wu CJ
Lien Pubmed
Résumé
Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice, and recapitulated the process of transformation from indolent CLL into large cell lymphoma (i.e. Richter's syndrome [RS]). Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed co-selection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, down-modulation of the receptor phosphatase PTEN, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.
Référence
Blood Cancer Discov. 2022 12 5;:
