RT Journal Article
T1 In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities
A1 Ten Hacken, Elisa
A1 Sewastianik, Tomasz
A1 Yin, Shanye
A1 Brunsting Hoffmann, Gabriela
A1 Gruber, Michaela
A1 Clement, Kendell
A1 Penter, Livius
A1 Redd, Robert A.
A1 Ruthen, Neil
A1 Hergalant, Sébastien
A1 Sholokhova, Alanna
A1 Fell, Geoffrey
A1 Parry, Erin M.
A1 Broséus, Julien
A1 Guieze, Romain
A1 Lucas, Fabienne
A1 Hernández Sánchez, María
A1 Baranowski, Kaitlyn
A1 Southard, Jackson
A1 Joyal, Heather
A1 Billington, Leah
A1 Carrasco, Ruben D.
A1 Wu, Catherine J.
AB 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.Significance: Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease.
PB American Association for Cancer Research
SN 2643-3230
YR 2022
FD 2022-12-06
LK https://hdl.handle.net/20.500.14352/111871
UL https://hdl.handle.net/20.500.14352/111871
LA eng
DS Docta Complutense
RD 5 abr 2025