Cell of origin associated classification of B-cell malignancies by gene signatures of the normal B-cell hierarchy

Abstract

Recent findings have suggested biological classification of B-cell malignancies as exemplified by the “activated B-cell-like” (ABC), the “germinal-center B-cell-like” (GCB) and primary mediastinal B-cell lymphoma (PMBL) subtypes of diffuse large B-cell lymphoma and “recurrent translocation and cyclin D” (TC) classification of multiple myeloma. Biological classification of B-cell derived cancers may be refined by a direct and systematic strategy where identification and characterization of normal B-cell differentiation subsets are used to define the cancer cell of origin phenotype. Here we propose a strategy combining multiparametric flow cytometry, global gene expression profiling and biostatistical modeling to generate B-cell subset specific gene signatures from sorted normal human immature, naive, germinal centrocytes and centroblasts, post-germinal memory B-cells, plasmablasts and plasma cells from available lymphoid tissues including lymph nodes, tonsils, thymus, peripheral blood and bone marrow. This strategy will provide an accurate image of the stage of differentiation, which prospectively can be used to classify any B-cell malignancy and eventually purify tumor cells. This report briefly describes the current models of the normal B-cell subset differentiation in multiple tissues and the pathogenesis of malignancies originating from the normal germinal B-cell hierarchy.

Keywords::

• Flow cytometry
• cell sorting
• gene expression profiling
• cell of origin
• cancer

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.

The scientific program was supported by grants from the Danish Research Agency (grant no. 99 00 771, no. 271-05-0286, no. 271-05-0537, no. 22-00-0314 and no. 2101-07-0007), the Multiple Myeloma Research Foundation (senior grant 2003-4, contract no. 14), the EU 6th FP (grant no LSHC-CT-2006-037602 to MSCNET, coordinator H. E. Johnsen), “The Obelske Family Foundation” and “The Spar Nord Foundation”.