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PMID: 16298817 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S. Review

Deregulated NOTCH signaling in acute T-cell lymphoblastic leukemia/lymphoma: new insights, questions, and opportunities.

International journal of hematology ·Vol. 82 ·No. 4 ·2005-11-00 ·Pages 295-301

Aster JC

Abstract

Recent work has shown that the majority of human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) have gain-of-function mutations in NOTCH1, a type I transmembrane receptor that normally signals through a gamma-secretase-dependent mechanism that relies on ligand-induced regulated intramembranous proteolysis. Cleavage by gamma-secretase releases the intracellular domain of NOTCH1 (ICN1), permitting it to translocate to the nucleus and form a short-lived transcriptional activation complex that is essential for normal T-cell development. Two types of mutations are prevalent in human T-ALL: extracellular domain mutations that increase ICN1 production and C-terminal mutations that sustain ICN1 action. Inhibitors of ICN1 production and activity abrogate the growth of established T-ALL cell lines, and a clinical trial of a NOTCH pathway inhibitor in patients with refractory T-ALL has opened recently. These insights raise a number of new questions relevant to T-ALL pathogenesis and offer exciting opportunities for rational targeted therapy.

MeSH Terms
Dimerization Gene Expression Regulation, Neoplastic Humans Leukemia-Lymphoma, Adult T-Cell/genetics Lymphoma, T-Cell/genetics Mutation Receptor, Notch1/genetics Signal Transduction/genetics T-Lymphocytes/immunology,physiology
Chemicals
Receptor, Notch1
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Aster Jon C
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. jaster@rics.bwh.harvard.edu
References (73)
73 references, click to expand
  1. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions.
    Blood. 2004 Sep 15;104(6):1696-702 PMID: 15187027
  2. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.
    J Biol Chem. 2001 Sep 21;276(38):35847-53 PMID: 11461910
  3. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.
    Mol Cell. 2004 Nov 19;16(4):509-20 PMID: 15546612
  4. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
    Cell. 1991 Aug 23;66(4):649-61 PMID: 1831692
  5. Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3 transgenic mice.
    EMBO J. 2000 Jul 3;19(13):3337-48 PMID: 10880446
  6. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor.
    J Biol Chem. 2001 Sep 14;276(37):34371-8 PMID: 11425854
  7. A gamma-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish.
    EMBO Rep. 2002 Jul;3(7):688-94 PMID: 12101103
  8. Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation.
    J Biol Chem. 2004 Mar 26;279(13):12876-82 PMID: 14709552
  9. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.
    J Exp Med. 1996 May 1;183(5):2283-91 PMID: 8642337
  10. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia.
    Cancer Cell. 2002 Feb;1(1):75-87 PMID: 12086890
  11. p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.
    Mol Cell Biol. 2002 Nov;22(22):7812-9 PMID: 12391150
  12. Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling.
    Nat Rev Mol Cell Biol. 2002 Sep;3(9):673-84 PMID: 12209127
  13. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.
    Genes Dev. 2002 Jun 1;16(11):1397-411 PMID: 12050117
  14. Gamma -secretase inhibitors repress thymocyte development.
    Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7487-91 PMID: 11416218
  15. Calcium depletion dissociates and activates heterodimeric notch receptors.
    Mol Cell Biol. 2000 Mar;20(5):1825-35 PMID: 10669757
  16. Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength.
    Immunity. 2001 Mar;14(3):253-64 PMID: 11290335
  17. Notch signaling controls the generation and differentiation of early T lineage progenitors.
    Nat Immunol. 2005 Jul;6(7):663-70 PMID: 15951813
  18. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling.
    Mol Cell Biol. 2003 Jan;23(2):655-64 PMID: 12509463
  19. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling.
    Nat Med. 2000 Nov;6(11):1278-81 PMID: 11062542
  20. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
    Nat Genet. 2000 Dec;26(4):484-9 PMID: 11101851
  21. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development.
    J Biol Chem. 2004 Mar 5;279(10 ):9417-23 PMID: 14672936
  22. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration.
    Annu Rev Neurosci. 2003;26:565-97 PMID: 12730322
  23. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.
    J Cell Biol. 2004 Oct 25;167(2):215-21 PMID: 15492044
  24. CSL-independent Notch signalling: a checkpoint in cell fate decisions during development?
    Curr Opin Genet Dev. 2002 Oct;12(5):524-33 PMID: 12200157
  25. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice.
    Blood. 2000 Sep 1;96(5):1906-13 PMID: 10961893
  26. Osteoblastic cells regulate the haematopoietic stem cell niche.
    Nature. 2003 Oct 23;425(6960):841-6 PMID: 14574413
  27. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development.
    Nat Immunol. 2005 Jul;6(7):671-9 PMID: 15951812
  28. Notch regulation of lymphocyte development and function.
    Nat Immunol. 2004 Mar;5(3):247-53 PMID: 14985712
  29. Presenilin-dependent gamma-secretase activity modulates thymocyte development.
    Proc Natl Acad Sci U S A. 2001 Jul 31;98(16):9312-7 PMID: 11470902
  30. Multiple niches for Notch in cancer: context is everything.
    Curr Opin Genet Dev. 2004 Feb;14(1):48-54 PMID: 15108805
  31. Notch1 expression in early lymphopoiesis influences B versus T lineage determination.
    Immunity. 1999 Sep;11(3):299-308 PMID: 10514008
  32. Analysis of TCR, pT alpha, and RAG-1 in T-acute lymphoblastic leukemias improves understanding of early human T-lymphoid lineage commitment.
    Blood. 2003 Apr 1;101(7):2693-703 PMID: 12446444
  33. Carboxy-terminal truncation activates glp-1 protein to specify vulval fates in Caenorhabditis elegans.
    Nature. 1991 Aug 29;352(6338):811-5 PMID: 1881436
  34. Nuclear access and action of notch in vivo.
    Cell. 1998 May 15;93(4):649-60 PMID: 9604939
  35. Notch signaling: cell fate control and signal integration in development.
    Science. 1999 Apr 30;284(5415):770-6 PMID: 10221902
  36. Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila.
    FASEB J. 2003 Jan;17(1):79-81 PMID: 12424225
  37. Regulation of notch signaling activity.
    Curr Biol. 2004 Feb 3;14 (3):R129-38 PMID: 14986688
  38. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation.
    Cancer Res. 2005 Mar 15;65(6):2353-63 PMID: 15781650
  39. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus.
    J Exp Med. 2001 Oct 1;194(7):1003-12 PMID: 11581321
  40. Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line.
    Mol Cell Biol. 2002 Jun;22(11):3927-41 PMID: 11997524
  41. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.
    Mol Cell. 2000 Feb;5(2):207-16 PMID: 10882063
  42. 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.
    Carcinogenesis. 2003 Jul;24(7):1257-68 PMID: 12807718
  43. Frequent provirus insertional mutagenesis of Notch1 in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notch1 for oncogenesis.
    Genes Dev. 1996 Aug 1;10(15):1930-44 PMID: 8756350
  44. Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice.
    Mol Cell Biol. 2000 Jun;20(11):3831-42 PMID: 10805726
  45. Deficient T cell fate specification in mice with an induced inactivation of Notch1.
    Immunity. 1999 May;10(5):547-58 PMID: 10367900
  46. Gamma-secretase: proteasome of the membrane?
    Nat Rev Mol Cell Biol. 2004 Jun;5(6):499-504 PMID: 15173829
  47. Transduction of Notch2 in feline leukemia virus-induced thymic lymphoma.
    J Virol. 1996 Nov;70(11):8071-80 PMID: 8892932
  48. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.
    Mol Cell Biol. 2001 Nov;21(21):7403-15 PMID: 11585921
  49. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome.
    Blood. 2002 Apr 1;99(7):2369-78 PMID: 11895769
  50. sel-10, a negative regulator of lin-12 activity in Caenorhabditis elegans, encodes a member of the CDC4 family of proteins.
    Genes Dev. 1997 Dec 1;11(23 ):3182-93 PMID: 9389650
  51. Germ-line tumor formation caused by activation of glp-1, a Caenorhabditis elegans member of the Notch family of receptors.
    Development. 1997 Feb;124(4):925-36 PMID: 9043073
  52. Presenilin is required for activity and nuclear access of Notch in Drosophila.
    Nature. 1999 Apr 8;398(6727):522-5 PMID: 10206646
  53. LAG-3 is a putative transcriptional activator in the C. elegans Notch pathway.
    Nature. 2000 May 18;405(6784):364-8 PMID: 10830967
  54. Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor.
    J Cell Biol. 2004 Jul 5;166(1):73-83 PMID: 15240571
  55. Gene expression profiling in T-cell acute lymphoblastic leukemia.
    Semin Hematol. 2003 Oct;40(4):274-80 PMID: 14582078
  56. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis.
    Cancer Cell. 2003 Jun;3(6):565-76 PMID: 12842085
  57. Presenilins in memory, Alzheimer's disease, and therapy.
    Neuron. 2004 Apr 22;42(2):189-92 PMID: 15091335
  58. Ligand-induced signaling in the absence of furin processing of Notch1.
    Dev Biol. 2001 Jan 15;229(2):494-502 PMID: 11150244
  59. Analysis of gain-of-function mutations of the lin-12 gene of Caenorhabditis elegans.
    Nature. 1990 Jul 12;346(6280):197-9 PMID: 2164160
  60. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance.
    Nat Immunol. 2005 Mar;6(3):314-22 PMID: 15665828
  61. The Notch1 receptor is cleaved constitutively by a furin-like convertase.
    Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8108-12 PMID: 9653148
  62. Perturbation of Ikaros isoform selection by MLV integration is a cooperative event in Notch(IC)-induced T cell leukemogenesis.
    Cancer Cell. 2003 Jun;3(6):551-64 PMID: 12842084
  63. Regulation of alphabeta/gammadelta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling.
    Immunity. 2004 May;20(5):611-22 PMID: 15142529
  64. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1.
    Mol Cell. 2000 Feb;5(2):197-206 PMID: 10882062
  65. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein.
    Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3338-45 PMID: 14766969
  66. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
    Nature. 1998 May 28;393(6683):382-6 PMID: 9620803
  67. Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.
    Immunity. 2001 Aug;15(2):225-36 PMID: 11520458
  68. Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats.
    Mol Cell Biol. 2004 Nov;24(21):9265-73 PMID: 15485896
  69. Mice lacking both presenilin genes exhibit early embryonic patterning defects.
    Genes Dev. 1999 Nov 1;13(21):2801-10 PMID: 10557208
  70. Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.
    Immunity. 2002 Feb;16(2):231-43 PMID: 11869684
  71. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells.
    Immunity. 2003 May;18(5):699-711 PMID: 12753746
  72. Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.
    Neuron. 2003 Apr 10;38(1):9-12 PMID: 12691659
  73. A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer.
    Blood. 2001 Dec 15;98(13):3793-9 PMID: 11739188
Article Info
Journal
International journal of hematology
Abbr.
Int J Hematol
ISSN
0925-5710
DOI
10.1532/IJH97.05096
Email
jaster@rics.bwh.harvard.edu
Published
2005-11-00
Pages
295-301
Language
English
Region
Japan
NLM ID
9111627
Subset
IM
External Links
PubMed source DOI: 10.1532/IJH97.05096 View journal details
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