In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A. Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M. Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather JoyalLeah Billington, Fara Faye D. Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A. Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S. Davids, Gad Getz, Kenneth J. Livak, Ivana Bozic, Donna S. Neuberg, Ruben D. Carrasco, Catherine J. Wu

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection 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, downmodulation of the PTEN phosphatase, 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.

Original languageEnglish
Pages (from-to)150-169
Number of pages20
JournalBlood cancer discovery
Volume4
Issue number2
DOIs
StatePublished - 1 Mar 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 American Association for Cancer Research.

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