title: Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy.
abstract: 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.
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Elisa
authors.initials: E
authors.lastname: Oricchio
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Man
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Boice
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Bouska
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Tim
authors.initials: T
authors.lastname: McKeithan
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.affiliation: Department of Pathology, Weill-Cornell Medical School, New York, NY 10065.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Venkatraman E
authors.initials: VE
authors.lastname: Seshan
authors.affiliation: Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Wing-Chung
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: R S K
authors.initials: RS
authors.lastname: Chaganti
authors.affiliation: Cancer Biology & Genetics Program, Computational Biology Program, Department of Medicine, Human Oncology and Pathogenesis Program, Genomics Core Facility, Molecular Pharmacology Program, Department of Pathology, Department of Epidemiology and Biostatistics, and Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Wendelh@mskcc.org.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C493966:CDKN2B protein, human; C417743:Cdkn2a protein, mouse; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; C052617:Bcl2 protein, mouse; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4