Reversible lymphomagenesis in conditionally c‐MYC expressing mice

It is well documented that deregulation of MYC leads to tumor development, yet many aspects of this process are only partially understood. We have established a transgenic mouse model in which c‐MYC is conditionally expressed in lymphoid cells using the tetracycline‐regulated system of gene regulation. Mice with continuously expressed transgenic c‐MYC died of invasive T‐ or B‐cell lymphomas within 4 months. Lymphomas developing in transgenic mice were c‐MYC dependent since doxycycline treatment led to tumor regression. Using transplantation of established tumor cell lines labeled with GFP, we followed the fate of neoplastic cells in recipients upon MYC inactivation. This approach allowed us to elucidate both apoptosis and differentiation as mechanisms of tumor elimination. Comparative genomic hybridization (CGH) and FISH analyses were performed in order to analyze possible chromosomal aberrations induced by c‐MYC. We observed that overexpression of c‐MYC is sufficient to induce recurrent patterns of genomic instability. The main observation was a gain of genomic material that corresponded to chromosome 15 in several T‐cell tumors, which could be identified as trisomy. © 2004 Wiley‐Liss, Inc.

[1]  M. Gossen,et al.  Co-regulation of two gene activities by tetracycline via a bidirectional promoter. , 1995, Nucleic acids research.

[2]  B. Nelson,et al.  The IL-2 Receptor Promotes Lymphocyte Proliferation and Induction of the c-myc, bcl-2, and bcl-x Genes Through the trans-Activation Domain of Stat51 , 2000, The Journal of Immunology.

[3]  M. Eilers,et al.  Control of cell proliferation by Myc. , 1998, Trends in cell biology.

[4]  H. Bujard,et al.  The B Lymphocyte-Specific Coactivator BOB.1/OBF.1 Is Required at Multiple Stages of B-Cell Development , 2001, Molecular and Cellular Biology.

[5]  G. Klein,et al.  Further studies on chromosome 15 trisomy in murine T‐cell lymphomas: Mapping of the relevant chromosome segment , 1988, International journal of cancer.

[6]  P. Leder,et al.  Translocations among antibody genes in human cancer. , 1983, Science.

[7]  Y. Jan,et al.  Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence , 1989, Cell.

[8]  M. Gossen,et al.  Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Bishop,et al.  Identification of virus-coded nonstructural polypeptides in bunyavirus-infected cells , 1982, Journal of virology.

[10]  J. Gray,et al.  Genome changes and gene expression in human solid tumors. , 2000, Carcinogenesis.

[11]  S. Efrat,et al.  Conditional transformation of a pancreatic beta-cell line derived from transgenic mice expressing a tetracycline-regulated oncogene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Pinkel,et al.  Comparative Genomic Hybridization for Molecular Cytogenetic Analysis of Solid Tumors , 2022 .

[13]  Robert Walgate,et al.  Proliferation , 1985, Nature.

[14]  J Piper,et al.  Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors , 1994, Genes, chromosomes & cancer.

[15]  R. Palmiter,et al.  The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice , 1985, Nature.

[16]  L. Loeb,et al.  Genomic instability and tumor progression: mechanistic considerations. , 1993, Advances in cancer research.

[17]  D. Felsher,et al.  Reversible tumorigenesis by MYC in hematopoietic lineages. , 1999, Molecular cell.

[18]  R. Eisenman,et al.  Max: a helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc. , 1991, Science.

[19]  M. Groudine,et al.  Control of c-myc regulation in normal and neoplastic cells. , 1991, Advances in cancer research.

[20]  M. Henriksson,et al.  Proteins of the Myc network: essential regulators of cell growth and differentiation. , 1996, Advances in cancer research.

[21]  P. Sideras,et al.  B Cell Development in the Spleen Takes Place in Discrete Steps and Is Determined by the Quality of B Cell Receptor–Derived Signals , 1999, The Journal of experimental medicine.

[22]  R. Cardiff,et al.  c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations , 2001, Nature Medicine.

[23]  M. Schlissel,et al.  Annexin V Binds to Positively Selected B Cells1 , 2001, The Journal of Immunology.

[24]  Thierry Fest,et al.  c-MYC overexpression in Ba/F3 cells simultaneously elicits genomic instability and apoptosis , 2002, Oncogene.

[25]  R. Eisenman,et al.  Mad: A heterodimeric partner for Max that antagonizes Myc transcriptional activity , 1993, Cell.

[26]  Chen-feng Qi,et al.  Burkitt Lymphoma in the Mouse , 2000, The Journal of experimental medicine.

[27]  T. Wirth,et al.  Functional analysis of defined mutations in the immunoglobulin heavy-chain enhancer in transgenic mice. , 1992, Nucleic acids research.

[28]  D. Green,et al.  Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. , 1992, Science.

[29]  R. Perlmutter,et al.  Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation , 1995, Cell.

[30]  H. Weintraub,et al.  Sequence-specific DNA binding by the c-Myc protein. , 1990, Science.

[31]  P. Leder,et al.  Consequences of widespread deregulation of the c-myc gene in transgenic mice: Multiple neoplasms and normal development , 1986, Cell.

[32]  T. Rabbitts,et al.  Effect of somatic mutation within translocated c-myc genes in Burkitt's lymphoma , 1984, Nature.

[33]  T. Ried,et al.  Abnormal rearrangement within the alpha/delta T-cell receptor locus in lymphomas from Atm-deficient mice. , 2000, Blood.

[34]  N. Krucher,et al.  Clonal evolution of N-methylnitrosourea-induced C57BL/6J thymic lymphomas by analysis of multiple genetic alterations. , 1997, Leukemia research.

[35]  S. McKnight,et al.  The leucine zipper: a hypothetical structure common to a new class of DNA binding proteins. , 1988, Science.

[36]  M. Eilers,et al.  Transcriptional repression by Myc. , 2003, Trends in cell biology.

[37]  Didier Picard,et al.  Chimaeras of Myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells , 1989, Nature.

[38]  E. Schröck,et al.  Previously hidden chromosome aberrations in T(12;15)-positive BALB/c plasmacytomas uncovered by multicolor spectral karyotyping. , 1997, Cancer research.

[39]  G. Carmichael,et al.  An alternative pathway for gene regulation by Myc , 1997, The EMBO journal.

[40]  G. Evan,et al.  The role of c-myc in cell growth. , 1993, Current opinion in genetics & development.

[41]  T. Ried,et al.  Abnormal rearrangement within the α/δ T-cell receptor locus in lymphomas from Atm-deficient mice , 2000 .

[42]  G. Wahl,et al.  c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. , 2002, Molecular cell.

[43]  D. Felsher,et al.  Transient excess of MYC activity can elicit genomic instability and tumorigenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[45]  M. Eilers,et al.  Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter. , 2001, Genes & development.

[46]  J Salvage,et al.  A matter of life and death. , 1981, Nursing times.

[47]  A. W. Harris,et al.  The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells , 1988, The Journal of experimental medicine.

[48]  E. Thompson,et al.  The many roles of c-Myc in apoptosis. , 1998, Annual review of physiology.

[49]  S. Lowe,et al.  Dissecting p53 tumor suppressor functions in vivo. , 2002, Cancer cell.