Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer.

Autor:	Ciampricotti M; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Karakousi T; Department of Pathology, New York University School of Medicine, New York, New York., Richards AL; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Quintanal-Villalonga À; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Karatza A; Perlmutter Cancer Center, New York University Langone Health, New York, New York., Caeser R; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Costa EA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York., Allaj V; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Manoj P; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Spainhower KB; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Kombak FE; Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York., Sanchez-Rivera FJ; Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York., Jaspers JE; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Zavitsanou AM; Department of Pathology, New York University School of Medicine, New York, New York., Maddalo D; Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York., Ventura A; Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York., Rideout WM; David H. Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts., Akama-Garren EH; David H. Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts., Jacks T; David H. Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts., Donoghue MTA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York., Sen T; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York., Oliver TG; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Poirier JT; Perlmutter Cancer Center, New York University Langone Health, New York, New York., Papagiannakopoulos T; Department of Pathology, New York University School of Medicine, New York, New York.; Perlmutter Cancer Center, New York University Langone Health, New York, New York., Rudin CM; Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Dec 01; Vol. 11 (12), pp. 3214-3229.
DOI:	10.1158/2159-8290.CD-21-0441
Abstrakt:	Small cell lung cancer (SCLC) has limited therapeutic options and an exceptionally poor prognosis. Understanding the oncogenic drivers of SCLC may help define novel therapeutic targets. Recurrent genomic rearrangements have been identified in SCLC, most notably an in-frame gene fusion between RLF and MYCL found in up to 7% of the predominant ASCL1-expressing subtype. To explore the role of this fusion in oncogenesis and tumor progression, we used CRISPR/Cas9 somatic editing to generate a Rlf-Mycl-driven mouse model of SCLC. RLF-MYCL fusion accelerated transformation and proliferation of murine SCLC and increased metastatic dissemination and the diversity of metastatic sites. Tumors from the RLF-MYCL genetically engineered mouse model displayed gene expression similarities with human RLF-MYCL SCLC. Together, our studies support RLF-MYCL as the first demonstrated fusion oncogenic driver in SCLC and provide a new preclinical mouse model for the study of this subtype of SCLC. Significance: The biological and therapeutic implications of gene fusions in SCLC, an aggressive metastatic lung cancer, are unknown. Our study investigates the functional significance of the in-frame RLF-MYCL gene fusion by developing a Rlf-Mycl-driven genetically engineered mouse model and defining the impact on tumor growth and metastasis. This article is highlighted in the In This Issue feature, p. 2945. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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