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

Authors: Oricchio, E.; Ciriello, G.; Jiang, M.; Boice, M. H.; Schatz, J. H.; Heguy, A.; Viale, A.; de Stanchina, E.; Teruya-Feldstein, J.; Bouska, A.; McKeithan, T.; Sander, C.; Tam, W.; Seshan, V. E.; Chan, W. C.; Chaganti, R. S. K.; Wendel, H. G.
Article 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. © 2014 Oricchio et al.
Journal Title: Journal of Experimental Medicine
Volume: 211
Issue: 7
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2014-06-30
Start Page: 1379
End Page: 1391
Language: English
DOI: 10.1084/jem.20132120
PROVIDER: scopus
PMCID: PMC4076578
PUBMED: 24913233
Notes: Export Date: 1 August 2014 -- CODEN: JEMEA -- Source: Scopus
Altmetric Score
MSK Authors
  1. Venkatraman Ennapadam Seshan
    288 Seshan
  2. Adriana Heguy
    85 Heguy
  3. Julie T Feldstein
    288 Feldstein
  4. Agnes Viale
    205 Viale
  5. Hans Guido Wendel
    60 Wendel
  6. Chris Sander
    196 Sander
  7. Raju S K Chaganti
    276 Chaganti
  8. Jonathan Harry Schatz
    14 Schatz
  9. Man Jiang
    12 Jiang
  10. Michael   Boice
    5 Boice