Blood Journal
Leading the way in experimental and clinical research in hematology

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

  1. Robert Kridel1,2,
  2. Barbara Meissner1,
  3. Sanja Rogic1,
  4. Merrill Boyle1,
  5. Adele Telenius1,
  6. Bruce Woolcock1,
  7. Jay Gunawardana1,2,
  8. Christopher Jenkins3,
  9. Chris Cochrane3,
  10. Susana Ben-Neriah1,
  11. King Tan1,
  12. Ryan D. Morin4,
  13. Stephen Opat1,
  14. Laurie H. Sehn1,
  15. Joseph M. Connors1,
  16. Marco A. Marra4,
  17. Andrew P. Weng3,*,
  18. Christian Steidl1,2,*, and
  19. Randy D. Gascoyne1,2,*
  1. 1Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC;
  2. 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC;
  3. 3Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC; and
  4. 4Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC


Mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma, is characterized by the hallmark translocation t(11;14)(q13;q32) and the resulting overexpression of cyclin D1 (CCND1). Our current knowledge of this disease encompasses frequent secondary cytogenetic aberrations and the recurrent mutation of a handful of genes, such as TP53, ATM, and CCND1. However, these findings insufficiently explain the biologic underpinnings of MCL. Here, we performed whole transcriptome sequencing on a discovery cohort of 18 primary tissue MCL samples and 2 cell lines. We found recurrent mutations in NOTCH1, a finding that we confirmed in an extension cohort of 108 clinical samples and 8 cell lines. In total, 12% of clinical samples and 20% of cell lines harbored somatic NOTCH1 coding sequence mutations that clustered in the PEST domain and predominantly consisted of truncating mutations or small frame-shifting indels. NOTCH1 mutations were associated with poor overall survival (P = .003). Furthermore, we showed that inhibition of the NOTCH pathway reduced proliferation and induced apoptosis in 2 MCL cell lines. In summary, we have identified recurrent NOTCH1 mutations that provide the preclinical rationale for therapeutic inhibition of the NOTCH pathway in a subset of patients with MCL.

  • Submitted November 11, 2011.
  • Accepted December 21, 2011.
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