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Paolella, Brenton R.

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Paolella

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Brenton R.

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Paolella, Brenton R.
Author's Publications: search.filters.isAuthorOfPublication.1b2e1eda-74f2-40d1-b4a5-e9c18e1fea7f

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    Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability
    (eLife Sciences Publications, Ltd, 2017) Paolella, Brenton R.; Gibson, William; Urbanski, Laura M; Alberta, John; Zack, Travis Ian; Bandopadhayay, Pratiti; Nichols, Caitlin; Agarwalla, Pankaj Kumar; Brown, Meredith S; Lamothe, Rebecca; Yu, Yong; Choi, Peter; Obeng, Esther A; Heckl, Dirk; Wei, Guo; Wang, Belinda; Tsherniak, Aviad; Vazquez, Francisca; Weir, Barbara Ann; Root, David E; Cowley, Glenn S; Buhrlage, Sara; Stiles, Charles; Ebert, Benjamin; Hahn, William; Reed, Robin; Beroukhim, Rameen
    Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency. DOI: http://dx.doi.org/10.7554/eLife.23268.001
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    MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism
    (2016) Bandopadhayay, Pratiti; Ramkissoon, Lori A.; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E.; Urbanski, Laura; O’Rourke, Ryan; Gibson, William; Pelton, Kristine; Ramkissoon, Shakti H.; Han, Harry J.; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E.; Kang, Yun Jee; Knoff, David; Paolella, Brenton R.; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M.; Federation, Alexander; Malkin, Hayley; Tracy, Adam; Seepo, Sara; Ducar, Matthew; Hummelen, Paul Van; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C.; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C.; Eberhart, Charles; Rodriguez, Fausto J.; Hill, D. Ashley; Mueller, Sabine; Haas-Kogan, Daphne; Phillips, Joanna J.; Santagata, Sandro; Stiles, Charles D.; Bradner, James E; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra; Goumnerova, Liliana; Waanders, Angela J.; Storm, Phillip B.; Kieran, Mark W.; Ligon, Keith; Beroukhim, Rameen; Resnick, Adam C.
    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.