TY - JOUR
T1 - Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy
AU - Oricchio, Elisa
AU - Ciriello, Giovanni
AU - Jiang, Man
AU - Boice, Michael H.
AU - Schatz, Jonathan H.
AU - Heguy, Adriana
AU - Viale, Agnes
AU - de Stanchina, Elisa
AU - Teruya-Feldstein, Julie
AU - Bouska, Alyssa
AU - McKeithan, Tim
AU - Sander, Chris
AU - Tam, Wayne
AU - Seshan, Venkatraman E.
AU - Chan, Wing Chung
AU - Chaganti, R. S.K.
AU - Wendel, Hans Guido
PY - 2014/6
Y1 - 2014/6
N2 - Loss 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.
AB - Loss 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.
UR - http://www.scopus.com/inward/record.url?scp=84903776028&partnerID=8YFLogxK
U2 - 10.1084/jem.20132120
DO - 10.1084/jem.20132120
M3 - Article
C2 - 24913233
AN - SCOPUS:84903776028
SN - 0022-1007
VL - 211
SP - 1379
EP - 1391
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -