Defective expression of Notch1 and Notch2 in connection to alterations of c-Myc and Ikaros in gamma-radiation-induced mouse thymic lymphomas.

Gamma-radiation-induced thymic lymphomas constitute a heterogeneous group of T-cell lymphomas. Some tumour suppressor genes and oncogenes have been shown to be defective in a fraction of such lymphomas, yet a considerable number of these remain elusive in terms of gene alterations. In the present work we present evidence that gamma-radiation-induced thymic lymphomas in (C57BL/6 J x BALB/c) F1 hybrid mice often exhibit increased levels of Notch1 expression, but, contrary to what was expected, they also exhibit a clearly reduced Notch2 mRNA expression, suggesting a cooperative antagonism of these genes. These results represent the first reported instance for the involvement of Notch2 inactivation in the development of thymic primary tumours while confirming the role of Notch1 as an activated oncogene. Additional analyses revealed that c-Myc over-expression and partial inactivation of Znfn1a1/Ikaros appear to be relevant events some how coupled to alterations in Notch genes inducing these kinds of tumours.

[1]  L. Girard,et al.  Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis. , 1996, Genes & development.

[2]  E. Salido,et al.  Mouse p73 gene maps to the distal part of chromosome 4 and might be involved in the progression of gamma-radiation-induced T-cell lymphomas. , 1999, Cancer research.

[3]  A. Capobianco,et al.  Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis. , 2003, Cancer cell.

[4]  K. Raj,et al.  The role of Notch in tumorigenesis: oncogene or tumour suppressor? , 2003, Nature Reviews Cancer.

[5]  N. Heerema,et al.  Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  K. Mita,et al.  Spectrum of Znfn1a1 (Ikaros) Inactivation and its Association with Loss of Heterozygosity in Radiogenic T-Cell Lymphomas in Susceptible B6C3F1 Mice , 2002, Radiation research.

[7]  M. Malumbres,et al.  Hypermethylation of the cell cycle inhibitor p15INK4b 3′-untranslated region interferes with its transcriptional regulation in primary lymphomas , 1999, Oncogene.

[8]  M. Malumbres,et al.  Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas. , 1999, Carcinogenesis.

[9]  J. Sklar,et al.  Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles , 1996, The Journal of experimental medicine.

[10]  E. Newcomb,et al.  p53 mutations in C57BL/6J murine thymic lymphomas induced by gamma-irradiation and N-methylnitrosourea. , 1992, Cancer research.

[11]  K. Georgopoulos,et al.  Zinc finger‐mediated protein interactions modulate Ikaros activity, a molecular control of lymphocyte development. , 1996, The EMBO journal.

[12]  R. Cardiff,et al.  p53 deficiency and misexpression of protein kinase CK2α collaborate in the development of thymic lymphomas in mice , 1998, Oncogene.

[13]  Hideki Ukai,et al.  Radiation-induced deletions in the 5' end region of Notch1 lead to the formation of truncated proteins and are involved in the development of mouse thymic lymphomas. , 2003, Carcinogenesis.

[14]  J. Rohn,et al.  Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma , 1996, Journal of virology.

[15]  K. Georgopoulos,et al.  The Ikaros gene encodes a family of functionally diverse zinc finger DNA-binding proteins , 1994, Molecular and cellular biology.

[16]  Jon C. Aster,et al.  Essential Roles for Ankyrin Repeat and Transactivation Domains in Induction of T-Cell Leukemia by Notch1 , 2000, Molecular and Cellular Biology.

[17]  A. Pellicer,et al.  Identification of a specific marker chromosome early in tumor development in gamma-irradiated C57BL/6J mice. , 1988, Leukemia.

[18]  S. Wakana,et al.  Radiation-Associated Loss of Heterozygosity at the Znfn1a1 (Ikaros) Locus on Chromosome 11 in Murine Thymic Lymphomas , 2000, Radiation research.

[19]  M. Malumbres,et al.  Characterization of the murine p19(ARF) promoter CpG island and its methylation pattern in primary lymphomas. , 2000, Carcinogenesis.

[20]  M. Herranz,et al.  Evidence of a possible epigenetic inactivation mechanism operating on a region of mouse chromosome 19 in γ-radiation-induced thymic lymphomas , 2001, Oncogene.

[21]  J. J. Steinberg,et al.  ras oncogenes and phenotypic staging in N-methylnitrosourea- and gamma-irradiation-induced thymic lymphomas in C57BL/6J mice. , 1988, Cancer research.

[22]  T. Miyazawa,et al.  Homozygous deletions and point mutations of the Ikaros gene in γ-ray-induced mouse thymic lymphomas , 1999, Oncogene.

[23]  S. Aizawa,et al.  Bcl11b is required for differentiation and survival of αβ T lymphocytes , 2003, Nature Immunology.

[24]  M. Malumbres,et al.  Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas , 1997, Oncogene.

[25]  K. Georgopoulos.  Haematopoietic cell-fate decisions, chromatin regulation and ikaros , 2002, Nature Reviews Immunology.

[26]  Takuro Nakamura,et al.  Bcl11a is essential for normal lymphoid development , 2003, Nature Immunology.

[27]  K. Georgopoulos,et al.  A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma , 1995, Cell.