The Journal of Experimental Medicine
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Published 3 December 2001. doi:10.1084/jem.194.11.1625
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© Rockefeller University Press, 0022-1007/2001/12/1625/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1625-1638


Original Article

Gene Expression Profiling of B Cell Chronic Lymphocytic Leukemia Reveals a Homogeneous Phenotype Related to Memory B Cells

Ulf Klein1, Yuhai Tu2, Gustavo A. Stolovitzky2, Michela Mattioli1, Giorgio Cattoretti1, Hervé Husson3, Arnold Freedman3, Giorgio Inghirami4, Lilla Cro5, Luca Baldini5, Antonino Neri5, Andrea Califano6 and Riccardo Dalla-Favera1

1 Institute for Cancer Genetics, Departments of Pathology and Genetics & Development, Columbia University, New York, NY 10032
2 IBM T.J. Watson Research Center, Yorktown Heights, New York, NY 10598
3 Department of Adult Oncology Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115
4 Department of Pathology, New York University Medical Center, New York, NY 10016
5 Ematologia 1, Department of Hematology, Ospedale Maggiore, I.R.C.C.S., Milan 20122, Italy
6 First Genetic Trust, Inc., Lyndhurst, NJ 07071

Address correspondence to Riccardo Dalla-Favera, Institute for Cancer Genetics, Columbia University, 1150 St. Nicholas Ave., New York, NY 10032. Phone: 212-304-7381; Fax: 212-304-5537; E-mail: rd10{at}columbia.edu

B cell–derived chronic lymphocytic leukemia (B-CLL) represents a common malignancy whose cell derivation and pathogenesis are unknown. Recent studies have shown that >50% of CLLs display hypermutated immunoglobulin variable region (IgV) sequences and a more favorable prognosis, suggesting that they may represent a distinct subset of CLLs which have transited through germinal centers (GCs), the physiologic site of IgV hypermutation. To further investigate the phenotype of CLLs, their cellular derivation and their relationship to normal B cells, we have analyzed their gene expression profiles using oligonucleotide-based DNA chip microarrays representative of ~12,000 genes. The results show that CLLs display a common and characteristic gene expression profile that is largely independent of their IgV genotype. Nevertheless, a restricted number of genes (<30) have been identified whose differential expression can distinguish IgV mutated versus unmutated cases and identify them in independent panels of cases. Comparison of CLL profiles with those of purified normal B cell subpopulations indicates that the common CLL profile is more related to memory B cells than to those derived from naive B cells, CD5+ B cells, and GC centroblasts and centrocytes. Finally, this analysis has identified a subset of genes specifically expressed by CLL cells of potential pathogenetic and clinical relevance.

Key Words: somatic hypermutation • germinal center • CD5 • DNA microarray • cluster analysis


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