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

Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response

  1. Stefano Monti,
  2. Kerry J. Savage,
  3. Jeffery L. Kutok,
  4. Friedrich Feuerhake,
  5. Paul Kurtin,
  6. Martin Mihm,
  7. Bingyan Wu,
  8. Laura Pasqualucci,
  9. Donna Neuberg,
  10. Ricardo C. T. Aguiar,
  11. Paola Dal Cin,
  12. Christine Ladd,
  13. Geraldine S. Pinkus,
  14. Gilles Salles,
  15. Nancy Lee Harris,
  16. Riccardo Dalla-Favera,
  17. Thomas M. Habermann,
  18. Jon C. Aster,
  19. Todd R. Golub, and
  20. Margaret A. Shipp
  1. From The Broad Institute, Cambridge, MA; the Department of Medical Oncology and the Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA; the Department of Pathology, Brigham and Women's Hospital, Boston, MA; the Department of Pathology and the Division of Hematology and Department of Medicine, Mayo Clinic, Rochester, MN; the Department of Pathology, Massachusetts General Hospital, Boston, MA; the Institute for Cancer Genetics, Columbia University, New York, NY; the Hematology Department, Centre Hospitalier Lyon-Sud, Lyon, France; and the Department of Pediatric Oncology, Dana-Farber Cancer Institute and Howard Hughes Medical Institute, Boston, MA.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. To identify robust and highly reproducible DL-BCL subtypes with comprehensive transcriptional signatures, we used a large series of newly diagnosed DLBCLs, whole genome arrays, and multiple clustering methods. Tumors were also analyzed for known common genetic abnormalities in DLBCL. There were 3 discrete subsets of DLBCL—“oxidative phosphorylation,” “B-cell receptor/proliferation,” and “host response” (HR)—identified characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/natural killer cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cell markers, and inflammatory mediators. HR DLB-CLs also contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/gamma interferon-induced lysosomal transferase–positive (GILT+) CD1a/CD123 dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, including fewer genetic abnormalities, younger age at presentation, and frequent splenic and bone marrow involvement. These studies identify tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets.

  • Submitted July 30, 2004.
  • Accepted November 1, 2004.
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