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

TitleIn Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities.
Publication TypeJournal Article
Year of Publication2023
AuthorsHacken ETen, Sewastianik T, Yin S, Hoffmann GBrunsting, Gruber M, Clement K, Penter L, Redd RA, Ruthen N, Hergalant S, Sholokhova A, Fell G, Parry EM, Broséus J, Guieze R, Lucas F, Hernández-Sánchez M, Baranowski K, Southard J, Joyal H, Billington L, Regis FFaye D, 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
JournalBlood Cancer Discov
Date Published2023 Mar 01
KeywordsAnimals, B-Lymphocytes, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Non-Hodgkin, Mice, Phosphatidylinositol 3-Kinases

UNLABELLED: 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. This article is highlighted in the In This Issue feature, p. 101.

Alternate JournalBlood Cancer Discov
PubMed ID36468984
PubMed Central IDPMC9975769
Grant ListK08 CA270085 / CA / NCI NIH HHS / United States
P01 CA206978 / CA / NCI NIH HHS / United States
R50 CA251956 / CA / NCI NIH HHS / United States
R21 CA267527 / CA / NCI NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700