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

Journal Article (Journal Article)

UNLABELLED: 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.

Full Text

Duke Authors

Cited Authors

  • Ciampricotti, M; Karakousi, T; Richards, AL; Quintanal-Villalonga, À; Karatza, A; Caeser, R; Costa, EA; Allaj, V; Manoj, P; Spainhower, KB; Kombak, FE; Sanchez-Rivera, FJ; Jaspers, JE; Zavitsanou, A-M; Maddalo, D; Ventura, A; Rideout, WM; Akama-Garren, EH; Jacks, T; Donoghue, MTA; Sen, T; Oliver, TG; Poirier, JT; Papagiannakopoulos, T; Rudin, CM

Published Date

  • December 1, 2021

Published In

Volume / Issue

  • 11 / 12

Start / End Page

  • 3214 - 3229

PubMed ID

  • 34344693

Pubmed Central ID

  • PMC8810895

Electronic International Standard Serial Number (EISSN)

  • 2159-8290

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-21-0441


  • eng

Conference Location

  • United States