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

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Rlf-Mycl Gene Fusion Drives Tumorigenesis and Metastasis in a Mouse Model of Small Cell Lung Cancer
Cancer Discovery ( IF 28.2 ) Pub Date : 2021-12-01 , DOI: 10.1158/2159-8290.cd-21-0441
Metamia Ciampricotti _{1,

2} , Triantafyllia Karakousi ₃ , Allison L Richards ₄ , Àlvaro Quintanal-Villalonga _{1,

2} , Angeliki Karatza ₅ , Rebecca Caeser _{1,

2} , Emily A Costa ₆ , Viola Allaj _{1,

2} , Parvathy Manoj _{1,

2} , Kyle B Spainhower ₇ , Faruk E Kombak ₈ , Francisco J Sanchez-Rivera ₉ , Janneke E Jaspers ₁₀ , Anastasia-Maria Zavitsanou ₃ , Danilo Maddalo ₉ , Andrea Ventura ₉ , William M Rideout ₁₁ , Elliot H Akama-Garren ₁₁ , Tyler Jacks ₁₁ , Mark T A Donoghue ₄ , Triparna Sen _{1,

2} , Trudy G Oliver ₇ , John T Poirier ₅ , Thales Papagiannakopoulos _{3,

5} , Charles M Rudin _{1,

2}

Affiliation

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.
Department of Pathology, New York University School of Medicine, New York, New York.
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Perlmutter Cancer Center, New York University Langone Health, New York, New York.
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Precision Pathology Center, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts.

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][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译：

Rlf-Mycl 基因融合驱动小细胞肺癌小鼠模型中的肿瘤发生和转移

小细胞肺癌 (SCLC) 的治疗选择有限，预后极差。了解 SCLC 的致癌驱动因素可能有助于确定新的治疗靶点。在 SCLC 中发现了复发性基因组重排，最显着的是在高达 7% 的主要表达 ASCL1 的亚型中发现了 RLF 和 MYCL 之间的框内基因融合。为了探索这种融合在肿瘤发生和肿瘤进展中的作用，我们使用 CRISPR/Cas9 体细胞编辑来生成 Rlf-Mycl 驱动的 SCLC 小鼠模型。RLF-MYCL 融合加速了小鼠 SCLC 的转化和增殖，增加了转移扩散和转移部位的多样性。来自 RLF-MYCL 基因工程小鼠模型的肿瘤显示出与人类 RLF-MYCL SCLC 的基因表达相似性。一起，我们的研究支持 RLF-MYCL 作为 SCLC 中第一个被证明的融合致癌驱动因素，并为研究这种 SCLC 亚型提供了新的临床前小鼠模型。意义：基因融合在 SCLC（一种侵袭性转移性肺癌）中的生物学和治疗意义尚不清楚。我们的研究通过开发 Rlf-Mycl 驱动的基因工程小鼠模型并确定对肿瘤生长和转移的影响来研究框内 RLF-MYCL 基因融合的功能意义。本文在 In This Issue 功能中突出显示，[p. 2945][1][1]：/lookup/volpage/11/2945?iss=12 一种侵袭性转移性肺癌，未知。我们的研究通过开发 Rlf-Mycl 驱动的基因工程小鼠模型并确定对肿瘤生长和转移的影响来研究框内 RLF-MYCL 基因融合的功能意义。本文在 In This Issue 功能中突出显示，[p. 2945][1][1]：/lookup/volpage/11/2945?iss=12 一种侵袭性转移性肺癌，未知。我们的研究通过开发 Rlf-Mycl 驱动的基因工程小鼠模型并确定对肿瘤生长和转移的影响来研究框内 RLF-MYCL 基因融合的功能意义。本文在 In This Issue 功能中突出显示，[p. 2945][1][1]：/lookup/volpage/11/2945?iss=12

更新日期：2021-12-02

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