Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy

J Exp Med. 2014 Jun 30;211(7):1379-91. doi: 10.1084/jem.20132120. Epub 2014 Jun 9.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics
  • Cyclin-Dependent Kinase Inhibitor p15 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Humans
  • Lymphoma, Follicular* / drug therapy
  • Lymphoma, Follicular* / genetics
  • Lymphoma, Follicular* / metabolism
  • Lymphoma, Follicular* / pathology
  • Male
  • Mice
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Retinoblastoma Protein* / genetics
  • Retinoblastoma Protein* / metabolism

Substances

  • CDKN2B protein, human
  • Cdkn2a protein, mouse
  • Cdkn2b protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p15
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proto-Oncogene Proteins c-bcl-2
  • Retinoblastoma Protein
  • Bcl2 protein, mouse
  • CDK4 protein, human
  • Cdk4 protein, mouse
  • Cyclin-Dependent Kinase 4