000202168 001__ 202168
000202168 005__ 20190317000028.0
000202168 0247_ $$2doi$$a10.1084/jem.20132120
000202168 022__ $$a1540-9538
000202168 037__ $$aARTICLE
000202168 245__ $$aFrequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy
000202168 260__ $$c2014
000202168 269__ $$a2014
000202168 336__ $$aJournal Articles
000202168 520__ $$aLoss of cell cycle controls is a hallmark of cancer and has a well-established role in aggressive B cell malignancies. However, the role of such lesions in indolent follicular lymphoma (FL) is unclear and individual lesions have been observed with low frequency. By analyzing genomic data from two large cohorts of indolent FLs, we identify a pattern of mutually exclusive (P = 0.003) genomic lesions that impair the retinoblastoma (RB) pathway in nearly 50% of FLs. These alterations include homozygous and heterozygous deletions of the p16/CDKN2a/b (7%) and RB1 (12%) loci, and more frequent gains of chromosome 12 that include CDK4 (29%). These aberrations are associated with high-risk disease by the FL prognostic index (FLIPI), and studies in a murine FL model confirm their pathogenic role in indolent FL. Increased CDK4 kinase activity toward RB1 is readily measured in tumor samples and indicates an opportunity for CDK4 inhibition. We find that dual CDK4 and BCL2 inhibitor treatment is safe and effective against available models of FL. In summary, frequent RB pathway lesions in indolent, high-risk FLs indicate an untapped therapeutic opportunity.
000202168 6531_ $$aLymphoma
000202168 6531_ $$aFollicular
000202168 6531_ $$aRetinoblastoma Protein
000202168 700__ $$0248688$$g253104$$aOricchio, Elisa
000202168 700__ $$aCiriello, Giovanni
000202168 700__ $$aJiang, Man
000202168 700__ $$aBoice, Michael H.
000202168 700__ $$aSchatz, Jonathan H.
000202168 700__ $$aHeguy, Adriana
000202168 700__ $$aViale, Agnes
000202168 700__ $$ade Stanchina, Elisa
000202168 700__ $$aTeruya-Feldstein, Julie
000202168 700__ $$aBouska, Alyssa
000202168 700__ $$aMcKeithan, Tim
000202168 700__ $$aSander, Chris
000202168 700__ $$aTam, Wayne
000202168 700__ $$aSeshan, Venkatraman E.
000202168 700__ $$aChan, Wing-Chung
000202168 700__ $$aChaganti, R. S. K.
000202168 700__ $$aWendel, Hans-Guido
000202168 773__ $$j211$$tThe Journal of experimental medicine$$k7$$q1379-91
000202168 8564_ $$uhttps://infoscience.epfl.ch/record/202168/files/J%20Exp%20Med-2014-Oricchio-1379-91.pdf$$zPublisher's version$$s3540329$$yPublisher's version
000202168 909C0 $$xU12997$$0252514$$pUPORICCHIO
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000202168 917Z8 $$x182396
000202168 937__ $$aEPFL-ARTICLE-202168
000202168 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000202168 980__ $$aARTICLE