Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes

The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of the cases of histological transformation. However, two different gene-expression profiles associated with the transformation process were defined, one in which c-myc and genes regulated by c-myc showed increased expression and one in which these same genes showed decreased expression. Further, there was a striking difference in gene-expression profiles between transformed DLBCL and de novo DLBCL, because the gene-expression profile of transformed DLBCL was more similar to their antecedent FL than to de novo DLBCL. This study demonstrates that transformation from FL to DLBCL can occur by alternative pathways and that transformed DLBCL and de novo DLBCL have very different gene-expression profiles that may underlie the different clinical behaviors of these two types of morphologically similar lymphomas.

[1]  A. Zetterberg,et al.  Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Larsson,et al.  c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. , 2000, Blood.

[3]  J Cairns,et al.  Cold Spring Harbor Symposia. , 1968, Science.

[4]  G. Prendergast,et al.  Mechanisms of apoptosis by c-Myc , 1999, Oncogene.

[5]  T. Colby,et al.  Histologic conversion in the non-Hodgkin's lymphomas. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  M. Llano,et al.  HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Lander,et al.  Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  P. Lorigan,et al.  Copy number gain at 12q12-14 may be important in the transformation from follicular lymphoma to diffuse large B cell lymphoma , 2001, British Journal of Cancer.

[9]  M. Gerretsen,et al.  A phase III randomised trial of cisplatinum, methotrextate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Liverpool Head and Neck Oncology Group. , 1990, British Journal of Cancer.

[10]  F. Marincola,et al.  High-fidelity mRNA amplification for gene profiling , 2000, Nature Biotechnology.

[11]  D. Longo,et al.  p53 mutation is associated with progression in follicular lymphomas. , 1993, Blood.

[12]  K. Offit,et al.  Intermediate- to high-grade histology of lymphomas carrying t(14;18) is associated with additional nonrandom chromosome changes. , 1987, Blood.

[13]  M. Raffeld,et al.  Clustered mutations in the transcriptional activation domain of Myc in 8q24 translocated lymphomas and their functional consequences. , 1995, Current topics in microbiology and immunology.

[14]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[15]  J. Woodgett,et al.  Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. , 1994, Oncogene.

[16]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[17]  M. Raffeld,et al.  A link between increased transforming activity of lymphoma-derived MYC mutant alleles, their defective regulation by p107, and altered phosphorylation of the c-Myc transactivation domain , 1995, Molecular and cellular biology.

[18]  S. Horning,et al.  The natural history of initially untreated low-grade non-Hodgkin's lymphomas. , 1984, The New England journal of medicine.

[19]  R. Gascoyne,et al.  Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. , 1998, Blood.

[20]  R. Warnke,et al.  Morphologic transformation of follicular lymphoma is associated with somatic mutation of the translocated Bcl-2 gene. , 1996, Blood.

[21]  U. Weidle,et al.  The transcriptional program of a human B cell line in response to Myc. , 2001, Nucleic acids research.

[22]  D. Weisenburger,et al.  Correlation of secondary cytogenetic abnormalities with histologic appearance in non-Hodgkin's lymphomas bearing t(14;18)(q32;q21). , 1988, Journal of the National Cancer Institute.

[23]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  p53 mutations are associated with histologic transformation of follicular lymphoma , 1993 .

[25]  G Flandrin,et al.  The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. , 1999, Annals of oncology : official journal of the European Society for Medical Oncology.

[26]  E. Campo,et al.  p16(INK4a) gene inactivation by deletions, mutations, and hypermethylation is associated with transformed and aggressive variants of non-Hodgkin's lymphomas. , 1998, Blood.

[27]  Ash A. Alizadeh,et al.  The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. , 1999, Cold Spring Harbor symposia on quantitative biology.

[28]  M. Oken,et al.  Multiple recurrent genomic defects in follicular lymphoma. A possible model for cancer. , 1987, The New England journal of medicine.

[29]  Elaine S. Jaffe,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[30]  I. Lossos,et al.  Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene. , 2000, Blood.

[31]  D. Longo,et al.  MYC rearrangements in histologically progressed follicular lymphomas. , 1992, Blood.

[32]  Gouri Nanjangud,et al.  Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas , 2001, Nature.