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

Elisa Oricchio, Giovanni Ciriello, Man Jiang, Michael H. Boice, Jonathan H Schatz, Adriana Heguy, Agnes Viale, Elisa de Stanchina, Julie Teruya-Feldstein, Alyssa Bouska, Tim McKeithan, Chris Sander, Wayne Tam, Venkatraman E. Seshan, Wing Chung Chan, R. S K Chaganti, Hans Guido Wendel

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1379-1391
Number of pages13
JournalJournal of Experimental Medicine
Volume211
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

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Follicular Lymphoma
Retinoblastoma
Therapeutics
Chromosomes, Human, Pair 12
Neoplasms
Cell Cycle Checkpoints
B-Lymphocytes
Phosphotransferases

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. / Oricchio, Elisa; Ciriello, Giovanni; Jiang, Man; Boice, Michael H.; Schatz, Jonathan H; Heguy, Adriana; Viale, Agnes; de Stanchina, Elisa; Teruya-Feldstein, Julie; Bouska, Alyssa; McKeithan, Tim; Sander, Chris; Tam, Wayne; Seshan, Venkatraman E.; Chan, Wing Chung; Chaganti, R. S K; Wendel, Hans Guido.

In: Journal of Experimental Medicine, Vol. 211, No. 7, 2014, p. 1379-1391.

Research output: Contribution to journalArticle

Oricchio, E, Ciriello, G, Jiang, M, Boice, MH, Schatz, JH, Heguy, A, Viale, A, de Stanchina, E, Teruya-Feldstein, J, Bouska, A, McKeithan, T, Sander, C, Tam, W, Seshan, VE, Chan, WC, Chaganti, RSK & Wendel, HG 2014, 'Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy', Journal of Experimental Medicine, vol. 211, no. 7, pp. 1379-1391. https://doi.org/10.1084/jem.20132120
Oricchio, Elisa ; Ciriello, Giovanni ; Jiang, Man ; Boice, Michael H. ; Schatz, Jonathan H ; Heguy, Adriana ; Viale, Agnes ; de Stanchina, Elisa ; Teruya-Feldstein, Julie ; Bouska, Alyssa ; McKeithan, Tim ; Sander, Chris ; Tam, Wayne ; Seshan, Venkatraman E. ; Chan, Wing Chung ; Chaganti, R. S K ; Wendel, Hans Guido. / Frequent disruption of the RB pathway in indolent follicular lymphoma suggests a new combination therapy. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 7. pp. 1379-1391.
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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

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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.

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