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  • Print publication year: 2006
  • Online publication date: September 2009

7 - Gene expression profiling in lymphoid malignancies

Summary

Introduction

The development of high throughput technologies and, in particular, of DNA microarrays led to a great leap forward in the understanding of complex biological processes, as highlighted in the previous chapters. Not surprisingly, this technology has also revealed exciting new insights in the field of lymphoid malignancies. Specifically, first steps have been taken towards a molecular classification of lymphomas, and gene expression-based survival predictors for lymphoma patients have been created that may prove useful in guiding future treatment decisions. Importantly, oncogenic pathways and relevant biological features of various lymphoma subtypes have been uncovered that may facilitate new targeted treatment approaches.

Traditionally, lymphoma classifications have been a topic of hot debate, and various conceptual frameworks have been used in the past to classify lymphomas in a clinically and biologically meaningful way [1]. Early attempts of lymphoma classification relied heavily on either morphological or clinical aspects (e.g., in the Rappaport classification or in the Working Formulation, respectively). In the Kiel classification, cytological and immunologic criteria were applied for the first time to classify lymphomas according to their derivation from the B- or T-cell lineage. The latest approaches to lymphoma classification, the Revised European-American Lymphoma (REAL) and World Health Organization (WHO) classifications, include morphological aspects, immunophenotype and clinical features, but also underlying genetic alterations to define lymphoma subtypes [2, 3]. For example, mantle cell lymphoma (MCL) is now regarded as a distinct subgroup of B-cell non-Hodgkin's lymphoma (B-NHL), characterized by the reciprocal chromosomal translocation t(11;14) that is present in virtually all cases [4].

REFERENCES
Harris, N. L., Jaffe, E. S., Diebold, J., Flandrin, G., Muller-Hermelink, H. K., and Vardiman, J.Lymphoma classification – from controversy to consensus: the R.E.A.L. and WHO Classification of lymphoid neoplasms. Ann. Oncol. 2000; 11, Suppl 1: 3–10.
Harris, N. L., Jaffe, E. S., Stein, H.et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361–92.
Jaffe, E. S., , H. N. L., Stein, H., and Vardiman, J. W. (eds.) World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001.
Campo, E., Raffeld, M., and Jaffe, E. S.Mantle-cell lymphoma. Semin. Hematol. 1999; 36: 115–27.
Dameshek, W.Chronic lymphocytic leukemia – an accumulative disease of immunolgically incompetent lymphocytes. Blood 1967; 29: Suppl: 566–84.
Fais, F., Ghiotto, F., Hashimoto, S.et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J. Clin. Invest. 1998; 102: 1515–25.
Oscier, D. G., Thompsett, A., Zhu, D., and Stevenson, F. K.Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997; 89: 4153–60.
Damle, R. N., Wasil, T., Fais, F.et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–7.
Hamblin, T. J., Davis, Z., Gardiner, A., Oscier, D. G., and Stevenson, F. K.Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–54.
Chiorazzi, N. and Ferrarini, M.B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu. Rev. Immunol. 2003; 21: 841–94.
Klein, U., Tu, Y., Stolovitzky, G. A.et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J. Exp. Med. 2001; 194: 1625–38.
Rosenwald, A., Alizadeh, A. A., Widhopf, G.et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J. Exp. Med. 2001; 194: 1639–47.
Alizadeh, A., Eisen, M., Davis, R. E.et al. The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 1999; 64: 71–8.
Chan, A. C., Iwashima, M., Turck, C. W., and Weiss, A.ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain. Cell 1992; 71: 649–62.
Wiestner, A., Rosenwald, A., Barry, T. S.et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101: 4944–51.
Crespo, M., Bosch, F., Villamor, N.et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N. Engl. J. Med. 2003; 348: 1764–75.
Orchard, J. A., Ibbotson, R. E., Davis, Z.et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004; 363: 105–11.
Rassenti, L. Z., Huynh, L., Toy, T. L.et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N. Engl. J. Med. 2004; 351: 893–901.
Haslinger, C., Schweifer, N., Stilgenbauer, S.et al. Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status. J. Clin. Oncol. 2004; 22: 3937–49.
Pettitt, A. R., Sherrington, P. D., Stewart, G., Cawley, J. C., Taylor, A. M., and Stankovic, T.p53 dysfunction in B-cell chronic lymphocytic leukemia: inactivation of ATM as an alternative to TP53 mutation. Blood 2001; 98: 814–22.
Stankovic, T., Weber, P., Stewart, G.et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 1999; 353: 26–9.
Stankovic, T., Stewart, G. S., Fegan, C.et al. Ataxia telangiectasia mutated-deficient B-cell chronic lymphocytic leukemia occurs in pregerminal center cells and results in defective damage response and unrepaired chromosome damage. Blood 2002; 99: 300–9.
Stankovic, T., Hubank, M., Cronin, D.et al. Microarray analysis reveals that TP53– and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses. Blood 2004; 103: 291–300.
Vallat, L., Magdelenat, H., Merle-Beral, H.et al. The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays. Blood 2003; 101: 4598–606.
Rosenwald, A., Chuang, E. Y., Davis, R. E.et al. Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood 2004; 104: 1428–34.
Dohner, H., Fischer, K., Bentz, M.et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood 1995; 85: 1580–9.
Wattel, E., Preudhomme, C., Hecquet, B.et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 1994; 84: 3148–57.
Raffeld, M. and Jaffe, E. S.bcl-1, t(11;14), and mantle cell-derived lymphomas. Blood 1991; 78: 259–63.
Swerdlow, S. H. and Williams, M. E.From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades. Hum. Pathol. 2002; 33: 7–20.
Rosenberg, C. L., Wong, E., Petty, E. M.et al. PRAD1, a candidate BCL1 oncogene: mapping and expression in centrocytic lymphoma. Proc. Natl Acad. Sci. USA 1991; 88: 9638–42.
Argatoff, L. H., Connors, J. M., Klasa, R. J., Horsman, D. E., and Gascoyne, R. D.Mantle cell lymphoma: a clinicopathologic study of 80 cases. Blood 1997; 89: 2067–78.
Bosch, F., Lopez-Guillermo, A., Campo, E.et al. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer 1998; 82: 567–75.
Lardelli, P., Bookman, M. A., Sundeen, J., Longo, D. L., and Jaffe, E. S.Lymphocytic lymphoma of intermediate differentiation. Morphologic and immunophenotypic spectrum and clinical correlations. Am. J. Surg. Pathol. 1990; 14: 752–63.
Dreyling, M. H., Bullinger, L., Ott, G.et al. Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res. 1997; 57: 4608–14.
Greiner, T. C., Moynihan, M. J., Chan, W. C.et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87: 4302–10.
Hernandez, L., Fest, T., Cazorla, M.et al. p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood 1996; 87: 3351–9.
Pinyol, M., Cobo, F., Bea, S.et al. p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas. Blood 1998; 91: 2977–84.
Raty, R., Franssila, K., Joensuu, H., Teerenhovi, L., and Elonen, E.Ki-67 expression level, histological subtype, and the International Prognostic Index as outcome predictors in mantle cell lymphoma. Eur. J. Haematol. 2002; 69: 11–20.
Rosenwald, A., Wright, G., Wiestner, A.et al. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell 2003; 3: 185–97.
Shaffer, A. L., Rosenwald, A., Hurt, E. M.et al. Signatures of the immune response. Immunity 2001; 15: 375–85.
Hofmann, W. K., Vos, S., Tsukasaki, K.et al. Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray. Blood 2001; 98: 787–94.
Martinez, N., Camacho, F. I., Algara, P.et al. The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res. 2003; 63: 8226–32.
Gary-Gouy, H., Harriague, J., Bismuth, G., Platzer, C., Schmitt, C., and Dalloul, A. H.Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production. Blood 2002; 100: 4537–43.
Vos, J., Thykjaer, T., Tarte, K.et al. Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays. Oncogene 2002; 21: 6848–57.
Katzenberger, T., Ott, G., Klein, T., Kalla, J., Muller-Hermelink, H. K., and Ott, M. M.Cytogenetic alterations affecting BCL6 are predominantly found in follicular lymphomas grade 3B with a diffuse large B-cell component. Am. J. Pathol. 2004; 165: 481–90.
Muller-Hermelink, H. K., Zettl, A., Pfeifer, W., and Ott, G.Pathology of lymphoma progression. Histopathology 2001; 38: 285–306.
Lossos, I. S., Alizadeh, A. A., Diehn, M.et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc. Natl Acad. Sci. USA 2002; 99: 8886–91.
Elenitoba-Johnson, K. S., Jenson, S. D., Abbott, R. T.et al. Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc. Natl Acad. Sci. USA 2003; 100: 7259–64.
Dave, S. S., Wright, G., Tan, B.et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N. Engl. J. Med. 2004; 351: 2159–69.
Glas, A. M., Kersten, M. J., Delahaye, L. J.et al. Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 2005; 105: 301–7.
Coiffier, B.Diffuse large cell lymphoma. Curr. Opin. Oncol. 2001; 13: 325–34.
Alizadeh, A. A., Eisen, M. B., Davis, R. E.et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11.
Eisen, M. B., Spellman, P. T., Brown, P. O., and Botstein, D.Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 1998; 95: 14863–8.
Rosenwald, A., Wright, G., Chan, W. C.et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002; 346: 1937–47.
Davis, R. E., Brown, K. D., Siebenlist, U., and Staudt, L. M.Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 2001; 194: 1861–74.
Bea, S., Zettl, A., Wright, G.et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 2005; 106(9): 3183–90.
Shipp, M. A., Ross, K. N., Tamayo, P.et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat. Med. 2002; 8: 68–74.
Wright, G., Tan, B., Rosenwald, A., Hurt, E. H., Wiestner, A., and Staudt, L. M.A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA 2003; 100: 9991–6.
Monti, S., Savage, K. J., Kutok, J. L.et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 2005; 105: 1851–61.