In vivo modeling of CLL transformation to Richter’s syndrome reveals convergent evolutionary paths and therapeutic vulnerabilities - Université de Lorraine Access content directly
Journal Articles Blood Cancer Discovery Year : 2023

In vivo modeling of CLL transformation to Richter’s syndrome reveals convergent evolutionary paths and therapeutic vulnerabilities

Robert Redd
Neil Ruthen
Alanna Sholokhova
Geoffrey Fell
Romain Guieze
Jackson Southard
Heather Joyal
Leah Billington
Elizabeth Witten
Mohamed Uduman
Haoxiang Lyu
Ivana Bozic
Donna Neuberg

Abstract

Abstract 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 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.

Dates and versions

hal-03950340 , version 1 (21-01-2023)

Identifiers

Cite

Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, et al.. In vivo modeling of CLL transformation to Richter’s syndrome reveals convergent evolutionary paths and therapeutic vulnerabilities. Blood Cancer Discovery, 2023, 4 (2), pp.150-169. ⟨10.1158/2643-3230.BCD-22-0082⟩. ⟨hal-03950340⟩
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