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

Autor:	Ten Hacken E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Sewastianik T; Harvard Medical School, Boston, Massachusetts.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland., Yin S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Hoffmann GB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Gruber M; CEMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria., Clement K; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Molecular Pathology Unit, Center for Cancer Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts.; Department of Pathology, Harvard Medical School, Boston, Massachusetts., Penter L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Hematology, Oncology, and Tumorimmunology, Campus Virchow Klinikum, Berlin, Charité - Universitätsmedizin Berlin (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin), Berlin, Germany., Redd RA; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Ruthen N; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, Massachusetts., Hergalant S; Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risques Environnementaux (N-GERE), Université de Lorraine, Nancy, France., Sholokhova A; Department of Applied Mathematics, University of Washington, Seattle, Washington., Fell G; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Parry EM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Broséus J; Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risques Environnementaux (N-GERE), Université de Lorraine, Nancy, France.; Université de Lorraine, CHRU-Nancy, Service d'Hématologie Biologique, Pôle Laboratoires, Nancy, France., Guieze R; CHU Clermont Ferrand, Clermont Ferrand, France., Lucas F; Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Hernández-Sánchez M; Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, Madrid, Spain., Baranowski K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Southard J; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, Massachusetts., Joyal H; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Billington L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Regis FFD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Witten E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Uduman M; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Knisbacher BA; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel., Li S; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, Massachusetts., Lyu H; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, Massachusetts., Vaisitti T; Department of Medical Sciences, University of Torino, Turin, Italy., Deaglio S; Department of Medical Sciences, University of Torino, Turin, Italy., Inghirami G; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York., Feugier P; Inserm UMRS1256 Nutrition-Génétique et Exposition aux Risques Environnementaux (N-GERE), Université de Lorraine, Nancy, France.; Université de Lorraine, CHRU-Nancy, Service d'Hématologie Biologique, Pôle Laboratoires, Nancy, France., Stilgenbauer S; Department III of Internal Medicine III, Division of CLL, Ulm University, Ulm, Germany., Tausch E; Department III of Internal Medicine III, Division of CLL, Ulm University, Ulm, Germany., Davids MS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Getz G; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts., Livak KJ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Translational Immunogenomics Lab, Dana-Farber Cancer Institute, Boston, Massachusetts., Bozic I; Department of Applied Mathematics, University of Washington, Seattle, Washington., Neuberg DS; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Carrasco RD; Harvard Medical School, Boston, Massachusetts.; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Wu CJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Blood cancer discovery [Blood Cancer Discov] 2023 Mar 01; Vol. 4 (2), pp. 150-169.
DOI:	10.1158/2643-3230.BCD-22-0082
Abstrakt:	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. (© 2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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