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Expression Profiling of B Cell Chronic Lymphocytic Leukemia Suggests Deficient

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Expression Profiling of B Cell Chronic Lymphocytic Leukemia Suggests Deficient Leukemia (2002) 16, 2429–2437 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu Expression profiling of B cell chronic lymphocytic leukemia suggests deficient CD1- mediated immunity, polarized cytokine response, altered adhesion and increased intracellular protein transport and processing of leukemic cells Z Zheng1, S Venkatapathy2, G Rao2 and CA Harrington2,3 1Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA; and 2Affymetrix, Inc, Santa Clara, CA, USA We used oligonucleotide microarrays to profile the expression are thought to derive from CD5+ expressing B cells.2,4 CD5- of chronic lymphocytic leukemia (CLL) B cells from eight expressing normal B cells are a small population of B cells patients compared with CD5-expressing normal B cells from localized at the edge of the germinal center within the mantle four donors and with pooled normal circulating B cells. Of 6790 5 genes examined, we identified 87 genes that were differentially zone of the secondary lymphoid follicles. They are con- expressed at least two-fold between CLL and the normal B sidered a good candidate for the normal counterpart of CLL cells. CLL cells significantly down-regulated transcripts from cells because they share several characteristics with the malig- CD1c and CD1d genes, which encode proteins known to nant CD5+ CLL cells. These include the propensity to produce present lipid antigen and mediate innate and adaptive immun- polyreactive, low-affinity IgM autoantibodies and the ity. The expression pattern was also consistent with reduced expression of the cross-reactive idiotypes in the antibody pro- signaling by interferon gamma but increased response to 2,6–8 interleukin 4 in leukemic cells. CLL cells increased the duced. Recently, human memory B cells have been pro- expression of several collagen-associated extracellular matrix posed as the normal counterpart of CLL-B cells.9 However, and adhesion molecules, up-regulated many genes involved in this alternative model has difficulty accounting for the above intracellular protein transport and processing, while down- features of CLL-B, and the large percentage of CLL cases with regulating genes involved in proliferation and metabolism. leukemic cells having unmutated immunoglubulin gene Based on the expression pattern, we propose that CLL-B cells prolong their survival through increased interaction with sur- would argue against an origin of post-germinal center stage vival factors such as IL-4, and through various mechanisms of cells such as the memory cells. The ideal normal counterpart evading the immune response, such as turning off the of CLL will likely remain a subject of discussion. At present, expression of CD1c and CD1d, reducing immunogenic the CD5+ B cell remains a reasonable candidate as the normal response to interferon gamma, inactivating T cell in B–T inter- counterpart of CLL and has been used as control cells in many action and increasing the expression of immunoglobulin recep- studies of CLL. tors which neutralize antibody-dependent cell-mediated cyto- toxicity. One approach to understanding the biological basis of CLL Leukemia (2002) 16, 2429–2437. doi:10.1038/sj.leu.2402711 pathophysiology would be to first correlate abnormal gene Keywords: CLL; microarray; expression profiling expression with the disease phenotypes. Recent advances in microarray technology allowfor comprehensive profiling of human cancer cells. This technique has been applied success- 10,11 Introduction fully in cancer classifications and diagnosis, and in gain- ing insights into functional pathways.12–14 Although B cell chronic leukemia is the most common leukemia in the expression profiling establishes only a correlative rather than western world, with approximately 10 000 new cases diag- causative role of identified genes in the biological process of nosed each year in the United States.1 It is characterized by the disease studied, experience has shown that the unique and the relentless accumulation in the blood, marrowand lymph- valuable global views of gene expression patterns, when oid tissues of mature monoclonal B lymphocytes that express coupled with available knowledge about gene functions, pro- the CD5 surface molecule. The leukemic CLL B cell accumu- vide the basis for formulating testable hypotheses about the 13,14 lation appears to be a result of defective apoptosis rather than disease pathways. Microarray profiling of hematological uncontrolled proliferation.2 CLL patients suffer immune malignancy for the purpose of exploring disease pathways deficiencies due to impaired humoral immunity characterized instead of disease classification has been reported recently in 15 by hypogammaglobulinemia. The leukemic B cells express a study of mantle cell lymphoma (MCL). However, a hetero- very lowlevels of surface IgM or IgD, and upon antigen stimu- geneous population of cells was profiled, complicating the lation, are unable to undergo somatic hypermutation and iso- interpretation of results and reducing the sensitivity of the 15 type switching. In addition, CLL patients frequently develop study. CLL cells are especially appropriate for microarray autoimmune diseases, suggesting immune dysregulation.3 analysis because of the relative ease in obtaining a purified, Unlike many forms of chronic and acute leukemia, CLL developmentally homogenous leukemic cell population in lacks recurrent reciprocal chromosomal translocations and large quantities. Recently, oligonucleotide microarray has distinctive patterns of oncogene or tumor suppressor gene been used to compare the expression patterns of CLL-B cells 9 expression. As a result, it has been difficult to identify the mol- with several normal B cell populations. That study, however, ecular events that lead to the disease phenotypes. CLL-B cells emphasized sample classification based on the overall expression pattern comparison. It did not focus on analyzing the potential roles of differentially expressed genes in the pathogenesis of CLL. Here, we report the use of oligonucleo- Correspondence: Z Zheng at the present address: Amersham Biosci- tide microarrays to compare gene expression profiles between ences, 928 E. Arques Ave, Sunnyvale, CA 94085, USA; Fax: (408) purified CLL-B cells and CD5-expressing normal B cells, and 773-8343; e.mail: [email protected] 3Present address: Vaccine and Gene Therapy Institute, Oregon Health between CLL and normal circulating B cells, as a way to ident- and Science University, Portland, OR 97006, USA ify potential molecular deregulations that may contribute to Received 17 February 2002; accepted 26 June 2002 the pathophysiology of CLL. The results of our study revealed Expression profiling of CLL Z Zheng et al 2430 that in CLL there was significant down-modulation of genes netic beads coupled with goat anti-IgG (Dynal) were involved in both protein and lipid antigen presentation. We employed, exactly as in the protocol used for the isolation of also observed reduced RNA levels for genes involved in inter- CD5+ cells from human tonsils. Based on gene expression pat- feron gamma response but increased transcript levels for IL-4 tern comparisons, no obvious difference in gene expression response genes. The profile also indicated reduced cell pro- can be attributed to the additional positive selection (see liferation and metabolism but increased intracellular protein Results and discussion below). transport and processing, as well as increased production of For additional comparison, we isolated human peripheral extracellular matrix and adhesion molecules in CLL-B cells blood B cells directly from fresh buffy coats obtained from relative to normal CD5+ B cells. The significance of these healthy donors (Stanford Blood Center, Stanford, CA, USA) abnormal gene expression patterns to CLL pathobiology is dis- using CD19-Dynabeads (Dynal). Purified B cells on beads cussed. were lysed directly in Trizol for total RNA extraction. Total RNA from seven individual buffy coats was pooled for sub- sequent Poly(A) selection. Materials and methods The use of all patient and normal samples above were according to an IRB approved protocol. Cell isolation and RNA extraction Normal CD5+ B cells were purified from four fresh human GeneChiparray expressionanalysis + tonsils collected from routine tonsillectomy procedures. CD5 + B cells like these were routinely used in most laboratories as Poly(A) RNA was selected using Oligotex mRNA midi kits (Qiagen, Valencia, CA, USA). Double-stranded cDNA was the normal controls in the studies of CLL-B cells. The tonsil + tissues were disrupted by gentle mechanical means, and the synthesized from poly(A) RNA with the SuperScript Choice resulting cell suspension was centrifuged through Ficoll– kit (Gibco) and oligo(dT) primers that contained a T7 RNA Ј Hypaque to obtain mononuclear cells. T cells were removed polymerase recognition sequence at the 5 end. Approxi- ␮ by two rounds of rosetting with an excess amount of fresh, mately 1 g of cDNA was subjected to in vitro transcription in neuroaminidase-treated sheep red blood cells (SRBC). Less the presence of biotinylated UTP and CTP (Enzo Diagnostic, than 1% of the remaining cells were CD2+ after rosetting. The Farmingdale, NY, USA) using the MegaScript T7 kit (Ambion, cells were then incubated with anti-CD5 MAb (Caltag, Bur- Austin, TX, USA). The labeled cRNA was fragmented and lingame, CA, USA) for 3–5 h at 4ºC, washed thoroughly in hybridized to a set of four oligonucleotide arrays (GeneChip PBS and incubated for 12
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