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

Stefano Monti, Kerry J. Savage, Jeffery L. Kutok, Friedrich Feuerhake, Paul Kurtin, Martin Mihm, Bingyan Wu, Laura Pasqualucci, Donna Neuberg, Ricardo C.T. Aguiar, Paola Dal Cin, Christine Ladd, Geraldine S. Pinkus, Gilles Salles, Nancy Lee Harris, Riccardo Dalla-Favera, Thomas M. Habermann, Jon C. Aster, Todd R. Golub, Margaret A. Shipp

Research output: Contribution to journalArticle

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 DLBCL 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.

Original languageEnglish (US)
Pages (from-to)1851-1861
Number of pages11
JournalBlood
Volume105
Issue number5
DOIs
StatePublished - Mar 1 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Monti, S., Savage, K. J., Kutok, J. L., Feuerhake, F., Kurtin, P., Mihm, M., Wu, B., Pasqualucci, L., Neuberg, D., Aguiar, R. C. T., Cin, P. D., Ladd, C., Pinkus, G. S., Salles, G., Harris, N. L., Dalla-Favera, R., Habermann, T. M., Aster, J. C., Golub, T. R., & Shipp, M. A. (2005). Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood, 105(5), 1851-1861. https://doi.org/10.1182/blood-2004-07-2947