Synapse - RLF-MYCL gene fusion drives tumorigenesis and metastasis in a mouse model of small cell lung cancer

RLF-MYCL gene fusion drives tumorigenesis and metastasis in a mouse model of small cell lung cancer Journal Article

Authors:	Ciampricotti, M.; Karakousi, T.; Richards, A. L.; Quintanal-Villalonga, A.; Karatza, A.; Caeser, R.; Costa, E. A.; Allaj, V.; Manoj, P.; Spainhower, K. B.; Kombak, F. E.; Sanchez-Rivera, F. J.; Jaspers, J. E.; Zavitsanou, A. M.; Maddalo, D.; Ventura, A.; Rideout, W. M. 3rd; Akama-Garren, E. H.; Jacks, T.; Donoghue, M. T. A.; Sen, T.; Oliver, T. G.; Poirier, J. T.; Papagiannakopoulos, T.; Rudin, C. M.
Article Title:	RLF-MYCL gene fusion drives tumorigenesis and metastasis in a mouse model of small cell lung cancer
Abstract:	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.
Keywords:	tumors; progression; trp53; therapy; suppressor; heterogeneity; inactivation; rb1; nfib
Journal Title:	Cancer Discovery
Volume:	11
Issue:	12
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2021-12-01
Start Page:	3214
End Page:	3229
Language:	English
ACCESSION:	WOS:000727278100001
DOI:	10.1158/2159-8290.Cd-21-0441
PROVIDER:	wos
PUBMED:	34344693
PMCID:	PMC8810895
Notes:	Article -- Source: Wos