Design and Methods Case Description

BACKGROUND AND OBJECTIVES Mantle cell lymphoma (MCL) cell lines are difficult to generate; only nine lines have been described so far and few of them have been thoroughly characterized. DESIGN AND METHODS We established MAVER-1, a new MCL cell line, obtained from a leukemic MCL harboring both a t(11;14) translocation and a MYC rearrangement, and used immunohistochemistry, flow cytometry, molecular biology and cytogenetic techniques in order to characterize the cell line precisely. RESULTS By immunohistochemistry and flow cytometry MAVER-1 displayed a classical MCL phenotype (IgM+, l+, CD5+, CD10-, CD19+, CD20+, CD23-, CD79a+, cyclin D1+) and genetic analysis showed a typical V/D/J rearrangement with naïve mutational status. According to both classic cytogenetic analysis and spectral karyotyping, MAVER-1 harbored the t(11;14) translocation associated with a complex karyotype. Molecular analysis by polymerase chain reactions showed that the t(11;14) breakpoint is within the major translocation cluster. Other important abnormalities of MAVER-1 include TP53 gene inactivation by a combined mutation of exon 8 and chromosome 17p13 deletion, ATM deletion, 8q24 (MYC) rearrangement and 8p22 deletion. INTERPRETATION AND CONCLUSIONS The new cell line will be useful for in vitro studies regarding MCL pathogenesis and drug sensitivity, as well as a diagnostic control material.

[1]  H. Tagawa,et al.  Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM , 2005, Oncogene.

[2]  A. Montpetit,et al.  Mutational and expression analysis of the chromosome 12p candidate tumor suppressor genes in pre-B acute lymphoblastic leukemia , 2004, Leukemia.

[3]  D. Steinemann,et al.  Molecular cytogenetic characterization of the mantle cell lymphoma cell line GRANTA-519. , 2004, Cancer genetics and cytogenetics.

[4]  G. Ott,et al.  Genomic DNA-chip hybridization in t(11;14)-positive mantle cell lymphomas shows a high frequency of aberrations and allows a refined characterization of consensus regions. , 2004, Blood.

[5]  D. Gold,et al.  Establishment and Characterization of a New Mantle Cell Lymphoma Cell Line M-1 , 2004, Leukemia & lymphoma.

[6]  F. Cavalli,et al.  Immunoglobulin heavy chain genes somatic hypermutations and chromosome 11q22‐23 deletion in classic mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research , 2004, British journal of haematology.

[7]  Kevin M Flanigan,et al.  Expression profiling of FSHD muscle supports a defect in specific stages of myogenic differentiation. , 2003, Human molecular genetics.

[8]  R. Siebert,et al.  Molecular Characterization of BCL6 Breakpoints in Primary Diffuse Large B‐cell Lymphomas of the Central Nervous System Identifies GAPD as Novel Translocation Partner , 2003, Brain pathology.

[9]  J. Bourhis,et al.  Multiple molecular mechanisms contribute to radiation sensitivity in mantle cell lymphoma , 2003, Oncogene.

[10]  D. Steinemann,et al.  Identification of candidate tumor‐suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms , 2003, Genes, chromosomes & cancer.

[11]  T. Barbui,et al.  Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen). , 2003, Blood.

[12]  T. McDonnell,et al.  Characterization of 4 mantle cell lymphoma cell lines. , 2003, Archives of pathology & laboratory medicine.

[13]  A. Ferrer,et al.  Abnormal expression of apoptosis‐related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma , 2003, British journal of haematology.

[14]  W. Sanger,et al.  Mantle Cell Lymphoma with 8q24 Chromosomal Abnormalities: a Report of 5 Cases with Blastoid Features , 2002, Modern Pathology.

[15]  H. Drexler,et al.  Malignant hematopoietic cell lines: in vitro models for the study of mantle cell lymphoma. , 2002, Leukemia research.

[16]  T. McDonnell,et al.  Establishment and characterization of a new mantle cell lymphoma cell line, Mino. , 2002, Leukemia research.

[17]  M. Cleary,et al.  The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. , 2002, Blood.

[18]  P. Lorigan,et al.  Identification of novel regions of amplification and deletion within mantle cell lymphoma DNA by comparative genomic hybridization , 2002, British journal of haematology.

[19]  R. Gascoyne,et al.  Cytogenetic Analysis in Mantle Cell Lymphoma: A Review of 214 Cases , 2002, Leukemia & lymphoma.

[20]  L. Medeiros,et al.  Cytogenetic findings in mantle cell lymphoma cases with a high level of peripheral blood involvement have a distinct pattern of abnormalities. , 2001, American journal of clinical pathology.

[21]  R. Siebert,et al.  Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma. , 2001, Blood.

[22]  H. Döhner,et al.  B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions. , 2001, Human molecular genetics.

[23]  E. Campo,et al.  BMI-1 gene amplification and overexpression in hematological malignancies occur mainly in mantle cell lymphomas. , 2001, Cancer research.

[24]  H. Drexler,et al.  Continuous hematopoietic cell lines as model systems for leukemia-lymphoma research. , 2000, Leukemia research.

[25]  G Flandrin,et al.  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, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  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.

[27]  A. Rosenwald,et al.  A biological role for deletions in chromosomal band 13q14 in mantle cell and peripheral t‐cell lymphomas? , 1999, Genes, chromosomes & cancer.

[28]  M. James,et al.  Molecular characterization of 11q deletions points to a pathogenic role of the ATM gene in mantle cell lymphoma. , 1999, Blood.

[29]  J. Gong,et al.  Cyclin D2 promoter disrupted by t(12;22)(p13;q11.2) during transformation of chronic lymphocytic leukaemia to non‐Hodgkin's lymphoma , 1999, British journal of haematology.

[30]  A. López-Guillermo,et al.  Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. , 1999, Blood.

[31]  T. Yoshino,et al.  Establishment and characterization of a mantle cell lymphoma cell line , 1998, British journal of haematology.

[32]  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.

[33]  W. Hiddemann,et al.  Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. , 1997, Cancer research.

[34]  A. Scarpa,et al.  p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin's lymphomas: a potential marker of p53 tumor-suppressor gene function. , 1996, Blood.

[35]  M. James,et al.  Molecular cytogenetic delineation of a novel critical genomic region in chromosome bands 11q22.3-923.1 in lymphoproliferative disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  D. Ledbetter,et al.  Multicolor Spectral Karyotyping of Human Chromosomes , 1996, Science.

[37]  F. Cavalli,et al.  Patterns of survival in mantle cell lymphoma. , 1995, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  F. Berger,et al.  Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas. , 1994, Blood.

[39]  K. Franssila,et al.  Two novel human B‐cell lymphoma lines of lymphatic follicle origin: Cytogenetic, molecular genetic and histopathological characterisation , 1994, European journal of haematology.

[40]  K. Offit,et al.  Deletions involving two distinct regions of 6q in B-cell non-Hodgkin lymphoma. , 1992, Blood.

[41]  E. Jaffe,et al.  Association of bcl-1 rearrangements with lymphocytic lymphoma of intermediate differentiation. , 1990, Blood.

[42]  G Hermanson,et al.  High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. , 1990, Science.

[43]  Y. Ohtsuki,et al.  The establishment of epstein‐barr virus nuclear antigen‐positive (SP‐50B) and epstein‐barr virus nuclear antigen‐negative (SP‐53) cell lines with t(11;14)(q13;q32) chromosome abnormality from an intermediate lymphocytic lymphoma , 1989, Cancer.

[44]  C. M. Steel,et al.  Characterization of a new non-Hodgkin's lymphoma cell line (NCEB-1) with a chromosomal (11:14) translocation [t(11:14)(q13;q32)]. , 1988, Blood.

[45]  M. Abe,et al.  Characterization and comparison of two newly established epstein‐barr virus‐negative lymphoma B‐cell lines: Surface markers, growth characteristics, cytogenetics, and transplantability , 1988, Cancer.

[46]  Y. Ohtsuki,et al.  Establishment of a new human B cell line carrying t(11;14) chromosome abnormality. , 1987, Japanese journal of cancer research : Gann.

[47]  R. Gascoyne,et al.  8q24 translocations in blastic transformation of mantle cell lymphoma. , 2000, Haematologica.

[48]  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.

[49]  J. Bartek,et al.  Potential role for concurrent abnormalities of the cyclin D1, p16CDKN2 and p15CDKN2B genes in certain B cell non-Hodgkin’s lymphomas. Functional studies in a cell line (Granta 519) , 1997, Leukemia.

[50]  B. Schlegelberger,et al.  Simultaneous presence of t(11;14) and a variant Burkitt's translocation in the terminal phase of a mantle cell lymphoma. , 1996, Leukemia.

[51]  M. Pericak-Vance,et al.  Regional mapping of facioscapulohumeral muscular dystrophy gene on 4q35: combined analysis of an international consortium. , 1992, American journal of human genetics.

[52]  Iscn.  International System for Human Cytogenetic Nomenclature , 1978 .