MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes.

Viability-promoting genes such as BCL2 play an important role in human cancer but do not directly cause aggressive tumors. BCL2 transgenic mice develop lymphoma at low frequency, hindering studies of tumorigenesis and its inhibition in the presence of such gene products. MCL1 is a member of the BCL2 family that is highly regulated endogenously and that promotes cell viability and immortalization when introduced exogenously. Mice expressing an MCL1 transgene in hematolymphoid tissues have now been monitored for an extended period and were found to develop lymphoma with long latency and at high probability (more than 85% over 2 years). In most cases, the disease was widely disseminated and of clonal B-cell origin. A variety of histologic subtypes were seen, prominently follicular lymphoma and diffuse large-cell lymphoma. MCL1 thus sets the stage for the development of lymphoma as does BCL2, disease occurring with high probability and recapitulating a spectrum of subtypes as seen in human patients. These findings with the transgene underscore the importance of the normal, highly regulated pattern of MCL1 expression, in addition to providing a model for studying tumorigenesis and its inhibition in the presence of a viability promoting BCL2 family member. (Blood. 2001;97:3902-3909)

[1]  R. Craig,et al.  Exon Skipping in Mcl-1 Results in a Bcl-2 Homology Domain 3 Only Gene Product That Promotes Cell Death* , 2000, The Journal of Biological Chemistry.

[2]  R. Craig,et al.  Myeloid Cell Leukemia 1 Is Phosphorylated through Two Distinct Pathways, One Associated with Extracellular Signal-regulated Kinase Activation and the Other with G2/M Accumulation or Protein Phosphatase 1/2A Inhibition* , 2000, The Journal of Biological Chemistry.

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

[4]  K. Roth,et al.  Mcl-1 deficiency results in peri-implantation embryonic lethality. , 2000, Genes & development.

[5]  C. Print,et al.  Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Bataille,et al.  IL‐6 up‐regulates Mcl‐1 in human myeloma cells through JAK / STAT rather than Ras / MAP kinase pathway , 1999, European journal of immunology.

[7]  Min-Liang Kuo,et al.  The Antiapoptotic Gene mcl-1 Is Up-Regulated by the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway through a Transcription Factor Complex Containing CREB , 1999, Molecular and Cellular Biology.

[8]  Robert A. Weinberg,et al.  Creation of human tumour cells with defined genetic elements , 1999, Nature.

[9]  M. García-Carrasco,et al.  Bcl-2 oncogene (B cell lymphoma/leukemia-2) levels correlate with systemic lupus erythematosus disease activity. , 1999, Anticancer Research.

[10]  S. Reddy,et al.  Characterization of Immortalized Osteoclast Precursors Developed from Mice Transgenic for Both bcl-XL and Simian Virus 40 Large T Antigen. , 1999, Endocrinology.

[11]  D. Vaux,et al.  Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. , 1999, Cancer research.

[12]  A. Yen,et al.  Regulation of MCL1 through a Serum Response Factor/Elk-1-mediated Mechanism Links Expression of a Viability-promoting Member of the BCL2 Family to the Induction of Hematopoietic Cell Differentiation* , 1999, The Journal of Biological Chemistry.

[13]  G. Srivastava,et al.  Progression of spontaneous lymphomas in SJL mice: monitoring in vivo clonal evolution with molecular markers in sequential splenic samples. , 1998, Laboratory investigation; a journal of technical methods and pathology.

[14]  R. Craig,et al.  Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. , 1998, Blood.

[15]  L. Silver,et al.  Transgenic N-myc mouse model for indolent B cell lymphoma: tumor characterization and analysis of genetic alterations in spontaneous and retrovirally accelerated tumors , 1998, Oncogene.

[16]  V. Godfrey,et al.  Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Craig,et al.  Expression of the antiapoptotic MCL1 gene product is regulated by a mitogen activated protein kinase-mediated pathway triggered through microtubule disruption and protein kinase C , 1998, Oncogene.

[18]  T. Knutsen,et al.  Cytogenetic changes in the progression of lymphoma. , 1998, Leukemia & lymphoma.

[19]  M. Kuo,et al.  mcl-1 Is an Immediate-Early Gene Activated by the Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Signaling Pathway and Is One Component of the GM-CSF Viability Response , 1998, Molecular and Cellular Biology.

[20]  I. Weissman,et al.  Mice defective in two apoptosis pathways in the myeloid lineage develop acute myeloblastic leukemia. , 1998, Immunity.

[21]  C. Rudin,et al.  A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas. , 1998, Cancer research.

[22]  C. Croce,et al.  Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with In vitro and In vivo chemoresponses. , 1998, Blood.

[23]  S. Korsmeyer,et al.  Hematopoietic malignancies demonstrate loss-of-function mutations of BAX. , 1998, Blood.

[24]  John Calvin Reed,et al.  Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. , 1998, Blood.

[25]  Joachim L. Schultze,et al.  Unbalanced Expression of Bcl-2 Family Proteins in Follicular Lymphoma: Contribution of CD40 Signaling in Promoting Survival , 1998 .

[26]  J. A. Quayle,et al.  Mcl-1 expression in human neutrophils: regulation by cytokines and correlation with cell survival. , 1998, Blood.

[27]  John Calvin Reed,et al.  Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell terminal differentiation. , 1997, Immunity.

[28]  D. Dorfman,et al.  Non‐Hodgkin's lymphomas: Current classification and management , 1997, CA: a cancer journal for clinicians.

[29]  J C Reed,et al.  Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. , 1997, Blood.

[30]  E. Smeland,et al.  Interleukin-13 in combination with CD40 ligand potently inhibits apoptosis in human B lymphocytes: upregulation of Bcl-xL and Mcl-1. , 1997, Blood.

[31]  John Calvin Reed,et al.  The apoptosis and proliferation of SAC-activated B cells by IL-10 are associated with changes in Bcl-2, Bcl-xL, and Mcl-1 expression. , 1997, Cellular immunology.

[32]  J C Reed,et al.  Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Phenotype , 1997, Science.

[33]  S. Korsmeyer,et al.  Bax suppresses tumorigenesis and stimulates apoptosis in vivo , 1997, Nature.

[34]  R. Craig,et al.  Mcl-1, a Bcl-2 family member, delays the death of hematopoietic cells under a variety of apoptosis-inducing conditions. , 1997, Blood.

[35]  A. Strasser,et al.  Lymphomas and plasmacytomas in transgenic mice involving bcl2, myc and v-abl. , 1997, Current Topics in Microbiology and Immunology.

[36]  C. Rudin,et al.  Apoptosis and disease: regulation and clinical relevance of programmed cell death. , 1997, Annual review of medicine.

[37]  A. Elefanty,et al.  Progenitor tumours from Emu‐bcl‐2‐myc transgenic mice have lymphomyeloid differentiation potential and reveal developmental differences in cell survival. , 1996, The EMBO journal.

[38]  R. Craig,et al.  MCL‐1, a member of the BCL‐2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation , 1996, Journal of cellular physiology.

[39]  E. Smeland,et al.  Expression of the Bcl-2 homologue Mcl-1 correlates with survival of peripheral blood B lymphocytes. , 1996, Cancer research.

[40]  R. Gascoyne,et al.  Short Communication Immunohistochemical Analysis of Mci-1 Protein in Human Tissues Differential Regulation of Mcl- 1 and Bcl-2 Protein Production Suggests a Unique Role for Mcl- 1 in Control of Programmed Cell Death In Vivo , 2007 .

[41]  D. Jong,et al.  Lymphoma-associated translocation t(14;18) in blood B cells of normal individuals. , 1995, Blood.

[42]  R. Craig,et al.  The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2 , 1995, The Journal of cell biology.

[43]  E. Cesarman,et al.  Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. , 1995, Blood.

[44]  R. Craig,et al.  Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells. , 1994, Cancer research.

[45]  D. Shibata,et al.  BCL2 translocation frequency rises with age in humans. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  D. Carney,et al.  Bcl-2 rearrangement in Hodgkin's disease and reactive lymph nodes. , 1994, American journal of clinical pathology.

[47]  T. Jacks,et al.  Enhanced cell survival and tumorigenesis. , 1994, Cold Spring Harbor Symposia on Quantitative Biology.

[48]  Z. Oltvai,et al.  Bcl-2 gene family and the regulation of programmed cell death. , 1994, Cold Spring Harbor symposia on quantitative biology.

[49]  R. Craig,et al.  MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Strasser,et al.  E mu-bcl-2 transgene facilitates spontaneous transformation of early pre-B and immunoglobulin-secreting cells but not T cells. , 1993, Oncogene.

[51]  Suzanne Cory,et al.  bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship , 1991, Cell.

[52]  D. Vaux,et al.  Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[53]  T. McDonnell,et al.  Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18) , 1991, Nature.

[54]  R. Craig,et al.  Improved coupling between proliferation‐arrest and differentiation‐induction in ML‐1 human myeloblastic leukemia cells , 1990, Journal of cellular physiology.

[55]  A. Strasser,et al.  Novel primitive lymphoid tumours induced in transgenic mice by cooperation between myc and bcl-2 , 1990, Nature.

[56]  S. Korsmeyer,et al.  Deregulated Bcl-2-immunoglobulin transgene expands a resting but responsive immunoglobulin M and D-expressing B-cell population , 1990, Molecular and cellular biology.

[57]  S. Korsmeyer,et al.  bcl-2-Immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation , 1989, Cell.

[58]  David L. Vaux,et al.  Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells , 1988, Nature.

[59]  Y. Tsujimoto,et al.  Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[60]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[61]  C. Taylor,et al.  Experimental models of lymphoproliferative disease. The mouse as a model for human non-Hodgkin's lymphomas and related leukemias. , 1983, The American journal of pathology.

[62]  A. Feinberg,et al.  A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. , 1983, Analytical biochemistry.

[63]  A. Menge,et al.  Monoclonal antibodies to human sperm antigens — II , 1982 .

[64]  S. Tonegawa,et al.  The role of DNA rearrangement and alternative RNA processing in the expression of immunoglobulin delta genes , 1981, Cell.

[65]  E. L. Green,et al.  Biology of the Laboratory Mouse , 1942 .

[66]  W. E. Heston.  Induction of Mammary Gland Tumors in Strain C57BL/He Mice by Isografts of Hypophyses , 1964 .