Constitutive activation of NF‐κB and T‐cell leukemia/lymphoma in Notch3 transgenic mice

The multiplicity of Notch receptors raises the question of the contribution of specific isoforms to T‐cell development. Notch3 is expressed in CD4−8− thymocytes and is down‐regulated across the CD4−8− to CD4+8+ transition, controlled by pre‐T‐cell receptor signaling. To determine the effects of Notch3 on thymocyte development, transgenic mice were generated, expressing lck promoter‐driven intracellular Notch3. Thymuses of young transgenics showed an increased number of thymocytes, particularly late CD4−8− cells, a failure to down‐regulate CD25 in post‐CD4−8− subsets and sustained activity of NF‐κB. Subsequently, aggressive multicentric T‐cell lymphomas developed with high penetrance. Tumors sustained characteristics of immature thymocytes, including expression of CD25, pTα and activated NF‐κB via IKKα‐dependent degradation of IκBα and enhancement of NF‐κB‐dependent anti‐apoptotic and proliferative pathways. Together, these data identify activated Notch3 as a link between signals leading to NF‐κB activation and T‐cell tumorigenesis. The phenotypes of pre‐malignant thymocytes and of lymphomas indicate a novel and particular role for Notch3 in co‐ordinating growth and differentiation of thymocytes, across the pre‐T/T cell transition, consistent with the normal expression pattern of Notch3.

[1]  I. Villey,et al.  RORγT, a thymus‐specific isoform of the orphan nuclear receptor RORγ / TOR, is up‐regulated by signaling through the pre‐T cell receptor and binds to the TEA promoter , 1999, European journal of immunology.

[2]  H. Pahl.  Activators and target genes of Rel/NF-κB transcription factors , 1999, Oncogene.

[3]  B. Rayet,et al.  Aberrant rel/nfkb genes and activity in human cancer , 1999, Oncogene.

[4]  U. Lendahl,et al.  The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. , 1999, Development.

[5]  J. Aster,et al.  Notch1 expression in early lymphopoiesis influences B versus T lineage determination. , 1999, Immunity.

[6]  David J. Anderson,et al.  Notch signalling controls pancreatic cell differentiation , 1999, Nature.

[7]  A Gulino,et al.  Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. , 1999, International immunology.

[8]  N. Tarantino,et al.  In Vivo Inhibition of NF-κB in T-Lineage Cells Leads to a Dramatic Decrease in Cell Proliferation and Cytokine Production and to Increased Cell Apoptosis in Response to Mitogenic Stimuli, But Not to Abnormal Thymopoiesis , 1999, The Journal of Immunology.

[9]  K. Tomita,et al.  The bHLH gene Hes1 is essential for expansion of early T cell precursors. , 1999, Genes & development.

[10]  H. Macdonald,et al.  Deficient T cell fate specification in mice with an induced inactivation of Notch1. , 1999, Immunity.

[11]  S. Artavanis-Tsakonas,et al.  Notch signaling: cell fate control and signal integration in development. , 1999, Science.

[12]  M. Tomonaga,et al.  Constitutive Activation of NF-κB in Primary Adult T-Cell Leukemia Cells , 1999 .

[13]  J. Buer,et al.  Pleiotropic changes controlled by the pre-T-cell receptor. , 1999, Current opinion in immunology.

[14]  M. Tomonaga,et al.  Constitutive Activation Of Nf- κ B In Primary Adult T-cell Leukemia Cells , 1999 .

[15]  C. Jongeneel,et al.  Impaired fetal thymocyte development after efficient adenovirus-mediated inhibition of NF-kappa B activation. , 1999, Journal of immunology.

[16]  W. Zong,et al.  The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-κB that blocks TNFα-induced apoptosis , 1999 .

[17]  M. Bevan,et al.  Correlating notch signaling with thymocyte maturation. , 1998, Immunity.

[18]  M. Bevan,et al.  RORgamma t, a novel isoform of an orphan receptor, negatively regulates Fas ligand expression and IL-2 production in T cells. , 1998, Immunity.

[19]  H. Macdonald,et al.  The role of the T‐cell receptor (TCR) in αβ/γδ lineage commitment: clues from intracellular TCR staining , 1998, Immunological reviews.

[20]  W. Greene,et al.  Human T-Cell Leukemia Virus Type 1 Tax Induction of NF-κB Involves Activation of the IκB Kinase α (IKKα) and IKKβ Cellular Kinases , 1998, Molecular and Cellular Biology.

[21]  D. F. Barber,et al.  Cutting Edge: The Expression In Vivo of a Second Isoform of pTα: Implications for the Mechanism of pTα Action , 1998, The Journal of Immunology.

[22]  A. Angelucci,et al.  The growth arrest and downregulation of c-myc transcription induced by ceramide are related events dependent on p21 induction, Rb underphosphorylation and E2F sequestering , 1998, Cell Death and Differentiation.

[23]  F. Oswald,et al.  NF-κB2 Is a Putative Target Gene of Activated Notch-1 via RBP-Jκ , 1998, Molecular and Cellular Biology.

[24]  M. Bevan,et al.  T-cell selection. , 1998, Current opinion in immunology.

[25]  M. Boothby,et al.  Perturbation of the T Lymphocyte Lineage In Transgenic Mice Expressing a Constitutive Repressor of Nuclear Factor (NF)-κB , 1997, The Journal of experimental medicine.

[26]  B. Fowlkes,et al.  Notch Activity Influences the αβ versus γδ T Cell Lineage Decision , 1997, Cell.

[27]  G. Weinmaster,et al.  An Activated Form of Notch Influences the Choice between CD4 and CD8 T Cell Lineages , 1996, Cell.

[28]  Seamus J. Martin,et al.  Suppression of TNF-α-Induced Apoptosis by NF-κB , 1996, Science.

[29]  U. Lendahl,et al.  Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development , 1996, Mechanisms of Development.

[30]  I. Screpanti,et al.  Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival. , 1996, Journal of immunology.

[31]  D. Carrasco,et al.  The v‐rel oncogene promotes malignant T‐cell leukemia/lymphoma in transgenic mice. , 1996, The EMBO journal.

[32]  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.

[33]  J. Laborda,et al.  T cell leukemia-associated human Notch/translocation-associated Notch homologue has I kappa B-like activity and physically interacts with nuclear factor-kappa B proteins in T cells , 1996, The Journal of experimental medicine.

[34]  D. Schatz,et al.  Productive T-cell receptor beta-chain gene rearrangement: coincident regulation of cell cycle and clonality during development in vivo. , 1996, Genes & development.

[35]  F. Bach,et al.  Inhibition of endothelial cell activation by adenovirus-mediated expression of I kappa B alpha, an inhibitor of the transcription factor NF-kappa B , 1996, The Journal of experimental medicine.

[36]  A. Passaniti,et al.  VEGF165 expressed by a replication-deficient recombinant adenovirus vector induces angiogenesis in vivo. , 1995, Circulation research.

[37]  A. Israël.  A role for phosphorylation and degradation in the control of NF-κB activity , 1995 .

[38]  I. Screpanti,et al.  Positive and negative regulation of the composite octamer motif of the interleukin 2 enhancer by AP-1, Oct-2, and retinoic acid receptor , 1994, The Journal of experimental medicine.

[39]  H. Macdonald,et al.  Double‐negative thymocyte subsets in CD3′ chain‐deficient mice: Absence of HSA+CD44−CD25− cells , 1994, European journal of immunology.

[40]  M J Owen,et al.  T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. , 1994, Immunity.

[41]  V. Bours,et al.  The oncoprotein Bcl‐3 can facilitate NF‐kappa B‐mediated transactivation by removing inhibiting p50 homodimers from select kappa B sites. , 1993, The EMBO journal.

[42]  M. Lenardo,et al.  Gene transcription in differentiating immature T cell receptor(neg) thymocytes resembles antigen-activated mature T cells , 1993, The Journal of experimental medicine.

[43]  A. Zlotnik,et al.  A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. , 1993, Journal of immunology.

[44]  V. Bours,et al.  The candidate oncoprotein Bcl-3 is an antagonist of pSO/NF-κB-mediated inhibition , 1992, Nature.

[45]  J. Sklar,et al.  TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms , 1991, Cell.

[46]  R. Boyd,et al.  Towards an integrated view of thymopoiesis. , 1991, Immunology today.

[47]  R. Perlmutter,et al.  Dissection of thymocyte signaling pathways by in vivo expression of pertussis toxin ADP‐ribosyltransferase. , 1990, The EMBO journal.

[48]  E. Jenkinson,et al.  Importance of IL-2 receptors in intra-thymic generation of cells expressing T-cell receptors , 1987, Nature.

[49]  B. Fowlkes,et al.  Notch Activity Influences the a versus ?d T Cell Lineage Decision , 1997 .