The Role of Notch Signaling in Multiple Myeloma

  • Dehui Xu
  • Jinsong Hu
  • Elke De Bruyne
  • Eline Menu
  • Karin Vanderkerken
  • Els Van Valckenborgh


The bone marrow (BM) microenvironment plays a critical role in the multiple myeloma (MM) cell growth and survival. As a highly conserved cell signaling system, the Notch pathway is considered to regulate cell-fate determination, stem cell self-renewal, proliferation, and apoptosis. Notch receptors and ligands are expressed both in MM cells and the BM microenvironment. In this review, we mainly discuss the canonical Notch signaling pathway including background and components of the signaling, its activation, the downstream targets, its regulation, and cross talk with other pathways. We further focus on the role of Notch signaling in multiple myeloma cell growth, angiogenesis, differentiation, drug resistance, bone disease, metastasis, and stem cell biology. A better understanding of Notch signaling in myeloma may provide new strategies to improve current treatment and overall survival.


Notch pathway Multiple myeloma Proliferation Angiogenesis Drug resistance Bone disease Differentiation Stem cell Bone marrow microenvironment 


  1. Allman D, Punt JA, Izon DJ et al (2002) An invitation to T and more: notch signaling in lymphopoiesis. Cell 109(Suppl):S1–11PubMedGoogle Scholar
  2. Androutsellis-Theotokis A, Leker RR, Soldner F et al (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826PubMedGoogle Scholar
  3. Armstrong F, Brunet de la Grange P, Gerby B et al (2009) NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity. Blood 113:1730–1740PubMedGoogle Scholar
  4. Artavanis-Tsakonas S, Matsuno K, Fortini ME (1995) Notch signaling. Science 268:225–232PubMedGoogle Scholar
  5. Bai S, Kopan R, Zou W et al (2008) NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 283:6509–6518PubMedGoogle Scholar
  6. Balakumaran A, Robey PG, Fedarko N et al (2010) Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis. Expert Rev Mol Diagn 10:465–480PubMedGoogle Scholar
  7. Benedito R, Roca C, Sorensen I et al (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135PubMedGoogle Scholar
  8. Bolos V, Blanco M, Medina V et al (2009) Notch signalling in cancer stem cells. Clin Transl Oncol 11:11–19PubMedGoogle Scholar
  9. Bommert K, Bargou RC, Stuhmer T (2006) Signalling and survival pathways in multiple myeloma. Eur J Cancer 42:1574–1580PubMedGoogle Scholar
  10. Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66:1631–1646PubMedGoogle Scholar
  11. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689PubMedGoogle Scholar
  12. Brou C, Logeat F, Gupta N et al (2000) A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5:207–216PubMedGoogle Scholar
  13. Burns CE, Traver D, Mayhall E et al (2005) Hematopoietic stem cell fate is established by the Notch-Runx pathway. Genes Dev 19:2331–2342PubMedGoogle Scholar
  14. Cheng X, Huber TL, Chen VC et al (2008) Numb mediates the interaction between Wnt and Notch to modulate primitive erythropoietic specification from the hemangioblast. Dev 135:3447–3458Google Scholar
  15. Chiba S (2006) Notch signaling in stem cell systems. Stem Cells 24:2437–2447PubMedGoogle Scholar
  16. Cruickshank MN, Ulgiati D (2010) The role of notch signaling in the development of a normal B-cell repertoire. Immunol Cell Biol 88:117–124PubMedGoogle Scholar
  17. Dallas MH, Varnum-Finney B, Delaney C et al (2005) Density of the Notch ligand Delta1 determines generation of B and T cell precursors from hematopoietic stem cells. J Exp Med 201:1361–1366PubMedGoogle Scholar
  18. Delaney C, Varnum-Finney B, Aoyama K et al (2005) Dose-dependent effects of the Notch ligand Delta1 on ex vivo differentiation and in vivo marrow repopulating ability of cord blood cells. Blood 106:2693–2699PubMedGoogle Scholar
  19. Demarest RM, Ratti F, Capobianco AJ (2008) It’s T-ALL about Notch. Oncogene 27:5082–5091PubMedGoogle Scholar
  20. Dezorella N, Pevsner-Fischer M, Deutsch V et al (2009) Mesenchymal stromal cells revert multiple myeloma cells to less differentiated phenotype by the combined activities of adhesive interactions and interleukin-6. Exp Cell Res 315:1904–1913PubMedGoogle Scholar
  21. Dotto GP (2008) Notch tumor suppressor function. Oncogene 27:5115–5123PubMedGoogle Scholar
  22. Dotto GP (2009) Crosstalk of Notch with p53 and p63 in cancer growth control. Nat Rev Cancer 9:587–595PubMedGoogle Scholar
  23. D’Souza B, Miyamoto A, Weinmaster G (2008) The many facets of Notch ligands. Oncogene 27(38):5148–5167PubMedGoogle Scholar
  24. Dufraine J, Funahashi Y, Kitajewski J (2008) Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27:5132–5137PubMedGoogle Scholar
  25. Edwards CM (2008) Wnt signaling: Bone’s defense against myeloma. Blood 112:216–217PubMedGoogle Scholar
  26. Edwards CM, Zhuang J, Mundy GR (2008) The pathogenesis of the bone disease of multiple myeloma. Bone 42:1007–1013PubMedGoogle Scholar
  27. Efferson CL, Winkelmann CT, Ware C et al (2010) Downregulation of notch pathway by a {gamma}-secretase inhibitor attenuates AKT/mammalian target of rapamycin signaling and glucose uptake in an ERBB2 transgenic breast cancer model. Cancer Res 70:2476–2484PubMedGoogle Scholar
  28. Ellisen LW, Bird J, West DC et al (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661PubMedGoogle Scholar
  29. Fehon RG, Kooh PJ, Rebay I et al (1990) Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell 61:523–534PubMedGoogle Scholar
  30. Fischer A, Gessler M (2007) Delta-Notch–and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 35:4583–4596PubMedGoogle Scholar
  31. Fiuza UM, Arias AM (2007) Cell and molecular biology of Notch. J Endocrinol 194:459–474PubMedGoogle Scholar
  32. Fortini ME, Bilder D (2009) Endocytic regulation of Notch signaling. Curr Opin Genet Dev 19:323–328PubMedGoogle Scholar
  33. Gal H, Amariglio N, Trakhtenbrot L et al (2006) Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 20:2147–2154PubMedGoogle Scholar
  34. Ghoshal P, Nganga AJ, Moran-Giuati J et al (2009) Loss of the SMRT/NCoR2 corepressor correlates with JAG2 overexpression in multiple myeloma. Cancer Res 69:4380–4387PubMedGoogle Scholar
  35. Gordon WR, Arnett KL, Blacklow SC (2008) The molecular logic of Notch signaling – a structural and biochemical perspective. J Cell Sci 121:3109–3119PubMedGoogle Scholar
  36. Grabher C, von Boehmer H, Look AT (2006) Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 6:347–359PubMedGoogle Scholar
  37. Guo YQ, Chen SL (2006) The significance of IGF-1, VEGF, IL-6 in multiple myeloma progression. Zhonghua Xue Ye Xue Za Zhi 27:231–234PubMedGoogle Scholar
  38. Guo D, Ye J, Dai J et al (2009) Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leukemia Res 33:678–685Google Scholar
  39. Hideshima T, Anderson KC (2002) Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2:927–937PubMedGoogle Scholar
  40. Hideshima T, Bergsagel PL, Kuehl WM et al (2004) Advances in biology of multiple myeloma: clinical applications. Blood 104:607–618PubMedGoogle Scholar
  41. Houde C, Li Y, Song L et al (2004) Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood 104:3697–3704PubMedGoogle Scholar
  42. Hsieh JJ, Zhou S, Chen L et al (1999) CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proc Natl Acad Sci USA96:23–28PubMedGoogle Scholar
  43. Ingram WJ, McCue KI, Tran TH et al (2008) Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene 27:1489–1500PubMedGoogle Scholar
  44. Iso T, Chung G, Hamamori Y et al (2002) HERP1 is a cell type-specific primary target of Notch. J Biol Chem 277:6598–6607PubMedGoogle Scholar
  45. Iso T, Kedes L, Hamamori Y (2003) HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194:237–255PubMedGoogle Scholar
  46. Jakob C, Sterz J, Zavrski I et al (2006) Angiogenesis in multiple myeloma. Eur J Cancer 42:1581–1590PubMedGoogle Scholar
  47. Jaleco AC, Neves H, Hooijberg E et al (2001) Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J Exp Med 194:991–1002PubMedGoogle Scholar
  48. Jang MS, Miao HX, Carlesso N et al (2004) Notch-1 regulates cell death independently of differentiation in murine erythroleukemia cells through multiple apoptosis and cell cycle pathways. J Cell Physiol 199:418–433PubMedGoogle Scholar
  49. Jarriault S, Brou C, Logeat F et al (1995) Signalling downstream of activated mammalian Notch. Nat 377:355–358Google Scholar
  50. Jeffery R, Mitchison NA (2001) IL-6 polymorphism, anti-IL-6 therapy and animal models of multiple myeloma. Cytokine 16:87PubMedGoogle Scholar
  51. Jin G, Zhang F, Chan KM et al (2011) MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development. Embo J 30:2281–2293PubMedGoogle Scholar
  52. Joshi S, Khan R, Sharma M et al (2011) Angiopoietin-2: a potential novel diagnostic marker in multiple myeloma. Clin Biochem 44:590–595PubMedGoogle Scholar
  53. Jundt F, Probsting KS, Anagnostopoulos I et al (2004) Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 103:3511–3515PubMedGoogle Scholar
  54. Kamakura S, Oishi K, Yoshimatsu T et al (2004) Hes binding to STAT3 mediates crosstalk between Notch and JAK-STAT signalling. Nat Cell Biol 6:547–554PubMedGoogle Scholar
  55. Kao HY, Ordentlich P, Koyano-Nakagawa N et al (1998) A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev 12:2269–2277PubMedGoogle Scholar
  56. Karsan A (2005) The role of notch in modeling and maintaining the vasculature. Can J Physiol Pharmacol 83:14–23PubMedGoogle Scholar
  57. Katoh M (2004) Identification and characterization of human HESL, rat Hesl and rainbow trout hesl genes in silico. Inter J Mol Med 14:747–751Google Scholar
  58. Katoh M (2006) NUMB is a break of WNT-Notch signaling cycle. Inter J Mol Med 18:517–521Google Scholar
  59. Katoh M (2007a) Integrative genomic analyses on HES/HEY family: Notch-independent HES1, HES3 transcription in undifferentiated ES cells, and Notch-dependent HES1, HES5, HEY1, HEY2, HEYL transcription in fetal tissues, adult tissues, or cancer. Inter J Oncol 31:461–466Google Scholar
  60. Katoh M (2007b) WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. Inter J Mol Med 19:197–201Google Scholar
  61. Katoh M, Katoh M (2006) Notch ligand, JAG1, is evolutionarily conserved target of canonical WNT signaling pathway in progenitor cells. Inter J Mol Med 17:681–685Google Scholar
  62. Kelly T, Borset M, Abe E et al (2000) Matrix metalloproteinases in multiple myeloma. Leukemia Lymphoma 37:273–281PubMedGoogle Scholar
  63. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049PubMedGoogle Scholar
  64. Klein B, Seckinger A, Moehler T et al (2011) Molecular pathogenesis of multiple myeloma: chromosomal aberrations, changes in gene expression, cytokine networks, and the bone marrow microenvironment. Recent Results Cancer Res 183:39–86PubMedGoogle Scholar
  65. Koch U, Radtke F (2007) Notch and cancer: a double-edged sword. Cell Mol Life Sci 64:2746–2762PubMedGoogle Scholar
  66. Kondoh K, Sunadome K, Nishida E (2007) Notch signaling suppresses p38 MAPK activity via induction of MKP-1 in myogenesis. J Biol Chem 282:3058–3065PubMedGoogle Scholar
  67. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233PubMedGoogle Scholar
  68. Kovall RA (2007) Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex. Curr Opin Struct Biol 17:117–127PubMedGoogle Scholar
  69. Krop IE, Kosh M, Fearen I et al (2006) Phase I pharmacokinetic, and pharmacodynamic trial of the novel oral notch inhibitor MK-0752 in patients with advanced breast cancer and other solid tumors. Breast Cancer Res Treat 100:S287–S287Google Scholar
  70. Kunnimalaiyaan M, Chen H (2007) Tumor suppressor role of Notch-1 signaling in neuroendocrine tumors. Oncologist 12:535–542PubMedGoogle Scholar
  71. Lage H (2008) An overview of cancer multidrug resistance: a still unsolved problem. Cell Mol Life Sci 65:3145–3167PubMedGoogle Scholar
  72. Lai EC (2002) Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins. Embo Rep 3:840–845PubMedGoogle Scholar
  73. Lamar E, Deblandre G, Wettstein D et al (2001) Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev 15:1885–1899PubMedGoogle Scholar
  74. Le Borgne R (2006) Regulation of Notch signalling by endocytosis and endosomal sorting. Curr Opin Cell Biol 18:213–222PubMedGoogle Scholar
  75. Le Bras S, Loyer N, Le Borgne R (2011) The multiple facets of ubiquitination in the regulation of notch signaling pathway. Traffic 12:149–161PubMedGoogle Scholar
  76. Leong KG, Karsan A (2006) Recent insights into the role of Notch signaling in tumorigenesis. Blood 107:2223–2233PubMedGoogle Scholar
  77. Li JL, Harris AL (2009) Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications. Front Biosci 14:3094–3110PubMedGoogle Scholar
  78. Li ZW, Chen H, Campbell RA et al (2008) NF-kappaB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol 15:391–399PubMedGoogle Scholar
  79. Li H, Wolfe MS, Selkoe DJ (2009) Toward structural elucidation of the gamma-secretase complex. Structure 17:326–334PubMedGoogle Scholar
  80. Lin S, Lai SL, Yu HH et al (2010) Lineage-specific effects of Notch/Numb signaling in post-embryonic development of the Drosophila brain. Dev 137:43–51Google Scholar
  81. Liu ZJ, Xiao M, Balint K et al (2006) Notch1 signaling promotes primary melanoma progression by activating mitogen-activated protein kinase/phosphatidylinositol 3-kinase-Akt pathways and up-regulating N-cadherin expression. Cancer Res 66:4182–4190PubMedGoogle Scholar
  82. Liu W, Singh SR, Hou SX (2010) JAK-STAT is restrained by Notch to control cell proliferation of the Drosophila intestinal stem cells. J Cell Biochem 109:992–999Google Scholar
  83. Lobov IB, Renard RA, Papadopoulos N et al (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA104:3219–3224PubMedGoogle Scholar
  84. Mancini SJ, Mantei N, Dumortier A et al (2005) Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105:2340–2342PubMedGoogle Scholar
  85. Mandinova A, Lefort K, Tommasi di Vignano A et al (2008) The FoxO3a gene is a key negative target of canonical Notch signalling in the keratinocyte UVB response. Embo J 27:1243–1254PubMedGoogle Scholar
  86. Matsui W, Wang Q, Barber JP et al (2008) Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 68:190–197PubMedGoogle Scholar
  87. Mazaleyrat SL, Fostier M, Wilkin MB et al (2003) Down-regulation of Notch target gene expression by suppressor of deltex. Dev Biol 255:363–372PubMedGoogle Scholar
  88. Mead TJ, Yutzey KE (2009) Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development. Proc Natl Acad Sci USA106:14420–14425PubMedGoogle Scholar
  89. Meads MB, Hazlehurst LA, Dalton WS (2008) The bone marrow microenvironment as a tumor sanctuary and contributor to drug resistance. Clin Cancer Res 14:2519–2526PubMedGoogle Scholar
  90. Meurette O, Stylianou S, Rock R et al (2009) Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res 69:5015–5022PubMedGoogle Scholar
  91. Moellering RE, Cornejo M, Davis TN et al (2009) Direct inhibition of the NOTCH transcription factor complex. Nat 462:182–188Google Scholar
  92. Mohr OL (1919) Character changes caused by mutation of an entire region of a Chromosome in Drosophila. Genetics 4:275–282PubMedGoogle Scholar
  93. Mumm JS, Schroeter EH, Saxena MT et al (2000) A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5:197–206PubMedGoogle Scholar
  94. Nefedova Y, Landowski TH, Dalton WS (2003) Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 17:1175–1182PubMedGoogle Scholar
  95. Nefedova Y, Cheng P, Alsina M et al (2004) Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103:3503–3510PubMedGoogle Scholar
  96. Nefedova Y, Sullivan DM, Bolick SC et al (2008) Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 111:2220–2229PubMedGoogle Scholar
  97. Niessen K, Fu Y, Chang L et al (2008) Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J Cell Biol 182:315–325PubMedGoogle Scholar
  98. Noguera-Troise I, Daly C, Papadopoulos NJ et al (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nat 444:1032–1037Google Scholar
  99. Noseda M, Chang L, McLean G et al (2004) Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: Role of p21(Cip1) repression. MolCell Biol 24:8813–8822Google Scholar
  100. Noseda M, Fu Y, Niessen K et al (2006) Smooth Muscle alpha-actin is a direct target of Notch/CSL. Circ Res 98:1468–1470PubMedGoogle Scholar
  101. Oldershaw RA, Tew SR, Russell AM et al (2008) Notch signaling through Jagged-1 is necessary to initiate chondrogenesis in human bone marrow stromal cells but must be switched off to complete chondrogenesis. Stem Cells 26:666–674PubMedGoogle Scholar
  102. Osipo C, Golde TE, Osborne BA et al (2008) Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Lab Investigation 88:11–17Google Scholar
  103. Oswald F, Liptay S, Adler G et al (1998) NF-kappaB2 is a putative target gene of activated Notch-1 via RBP-Jkappa. Mol Cell Biol 18:2077–2088PubMedGoogle Scholar
  104. Palomero T, Lim WK, Odom DT et al (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA103:18261–18266PubMedGoogle Scholar
  105. Pannequin J, Bonnans C, Delaunay N et al (2009) The wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells. Cancer Res 69:6065–6073PubMedGoogle Scholar
  106. Pece S, Serresi M, Santolini E et al (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167:215–221PubMedGoogle Scholar
  107. Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196–208PubMedGoogle Scholar
  108. Pirot P, van Grunsven LA, Marine JC et al (2004) Direct regulation of the Nrarp gene promoter by the Notch signaling pathway. Biochem Biophys Res Commun 322:526–534PubMedGoogle Scholar
  109. Podar K, Chauhan D, Anderson KC (2009) Bone marrow microenvironment and the identification of new targets for myeloma therapy. Leukemia 23:10–24PubMedGoogle Scholar
  110. Puthier D, Derenne S, Barille S et al (1999) Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Haematol 107:392–395PubMedGoogle Scholar
  111. Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767PubMedGoogle Scholar
  112. Radtke F, Wilson A, MacDonald HR (2004) Notch signaling in T- and B-cell development. Curr Opin Immunol 16:174–179PubMedGoogle Scholar
  113. Ramakrishnan V, Ansell S, Haug J et al (2011) MRK003, a gamma-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin’s lymphoma. Leukemia 26:340–348PubMedGoogle Scholar
  114. Rampal R, Li AS, Moloney DJ et al (2005) Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J BiolChem 280:42454–42463Google Scholar
  115. Reedijk MJ, Cohen B, Shimizu M et al (2009) Cyclin D1 is a direct target of JAG-mediated notch signaling in breast cancer. Cancer Res 69:641s–641sGoogle Scholar
  116. Reguart N (2009) Identifying cancer stem cells prognostic markers: Notch. J Thoracic Oncol 4:S82–S83Google Scholar
  117. Ridgway J, Zhang G, Wu Y et al (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nat 444:1083–1087Google Scholar
  118. Rodilla V, Villanueva A, Obrador-Hevia A et al (2009) Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc Natl Acad Sci USA106:6315–6320PubMedGoogle Scholar
  119. Ronchini C, Capobianco AJ (2001) Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol 21:5925–5934PubMedGoogle Scholar
  120. Roy M, Pear WS, Aster JC (2007) The multifaceted role of Notch in cancer. Curr Opin Genet Dev 17:52–59PubMedGoogle Scholar
  121. Sahlgren C, Gustafsson MV, Jin S et al (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA105:6392–6397PubMedGoogle Scholar
  122. San-Juan BP, Baonza A (2011) The bHLH factor deadpan is a direct target of Notch signaling and regulates neuroblast self-renewal in Drosophila. Dev Biol 352:70–82PubMedGoogle Scholar
  123. Santos MA, Sarmento LM, Rebelo M et al (2007) Notch1 engagement by Delta-like-1 promotes differentiation of B lymphocytes to antibody-secreting cells. Proc Natl Acad Sci USA104:15454–15459PubMedGoogle Scholar
  124. Schuster-Gossler K, Harris B, Johnson KR et al (2009) Notch signalling in the paraxial mesoderm is most sensitive to reduced Pofut1 levels during early mouse development. Bmc Dev Biol 9:6PubMedGoogle Scholar
  125. Schwarzenbach H (2002) Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma. Med Oncol 19:87–104PubMedGoogle Scholar
  126. Schwarzer R, Kaiser M, Acikgoez O et al (2008) Notch inhibition blocks multiple myeloma cell-induced osteoclast activation. Leukemia 22:2273–2277PubMedGoogle Scholar
  127. Shih IM, Wang TL (2007) Notch signaling, gamma-secretase inhibitors, and cancer therapy. Cancer Res 67:1879–1882PubMedGoogle Scholar
  128. Shimizu M, Cohen B, Goldvasser P et al (2011) Plasminogen activator uPA is a direct transcriptional target of the JAG1-Notch receptor signaling pathway in breast cancer. Cancer Res 71:277–286PubMedGoogle Scholar
  129. Sivasankaran B, Degen M, Ghaffari A et al (2009) Tenascin-C is a novel RBPJkappa-induced target gene for Notch signaling in gliomas. Cancer Res 69:458–465PubMedGoogle Scholar
  130. Six EM, Ndiaye D, Sauer G et al (2004) The notch ligand Delta1 recruits Dlg1 at cell-cell contacts and regulates cell migration. J Biol Chem 279:55818–55826PubMedGoogle Scholar
  131. Sjolund J, Manetopoulos C, Stockhausen MT et al (2005) The Notch pathway in cancer: differentiation gone awry. Eur J Cancer 41:2620–2629PubMedGoogle Scholar
  132. Smith EM, Akerblad P, Kadesch T et al (2005) Inhibition of EBF function by active Notch signaling reveals a novel regulatory pathway in early B-cell development. Blood 106:1995–2001PubMedGoogle Scholar
  133. Stahl M, Uemura K, Ge C et al (2008) Roles of Pofut1 and O-fucose in mammalian Notch signaling. J Biol Chem 283:13638–13651PubMedGoogle Scholar
  134. Stanley P, Guidos CJ (2009) Regulation of Notch signaling during T- and B-cell development by O-fucose glycans. Immunological Rev 230:201–215Google Scholar
  135. Stylianou S, Clarke RB, Brennan K (2006a) Aberrant activation of notch signaling in human breast cancer. Cancer Res 66:1517–1525PubMedGoogle Scholar
  136. Stylianou S, Collu GM, Clarke RB et al (2006b) Aberrant activation of Notch signalling in human breast cancer. Breast Cancer Res 8:S3–S3Google Scholar
  137. Suchting S, Freitas C, le Noble F et al (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA104:3225–3230PubMedGoogle Scholar
  138. Suda T, Kamiyama S, Suzuki M et al (2004) Molecular cloning and characterization of a human multisubstrate specific nucleotide-sugar transporter homologous to Drosophila fringe connection. J Biol Chem 279:26469–26474PubMedGoogle Scholar
  139. Suzuki T, Chiba S (2005) Notch signaling in hematopoietic stem cells. Inter J Hematol 82:285–294Google Scholar
  140. Takeuchi T, Adachi Y, Ohtsuki Y (2005) Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma. Am J Pathol 166:1817–1826PubMedGoogle Scholar
  141. Tammela T, Enholm B, Alitalo K et al (2005) The biology of vascular endothelial growth factors. Cardiovasc Res 65:550–563PubMedGoogle Scholar
  142. Tanigaki K, Kuroda K, Han H et al (2003) Regulation of B cell development by Notch/RBP-J signaling. Semin Immunol 15:113–119PubMedGoogle Scholar
  143. Thurston G, Kitajewski J (2008) VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 99:1204–1209PubMedGoogle Scholar
  144. Thurston G, Noguera-Troise I, Yancopoulos GD (2007) The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7:327–331PubMedGoogle Scholar
  145. Tun T, Hamaguchi Y, Matsunami N et al (1994) Recognition sequence of a highly conserved DNA binding protein RBP-J kappa. Nucleic Acids Res 22:965–971PubMedGoogle Scholar
  146. Ullah MF (2008) Cancer multidrug resistance (MDR): a major impediment to effective chemotherapy. Asian Pac J Cancer Prev 9:1–6PubMedGoogle Scholar
  147. Vacca A, Ribatti D (2006) Bone marrow angiogenesis in multiple myeloma. Leukemia 20:193–199PubMedGoogle Scholar
  148. Van de Walle I, De Smet G, Gartner M et al (2011) Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. Blood 117:4449–4459PubMedGoogle Scholar
  149. Van Es JH, van Gijn ME, Riccio O et al (2005) Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435:959–963PubMedGoogle Scholar
  150. Van Tetering G, van Diest P, Verlaan I et al (2009) Metalloprotease ADAM10 is required for Notch1 site 2 cleavage. J Biol Chem 284:31018–31027PubMedGoogle Scholar
  151. Van Valckenborgh E, Lub S, Xu D et al (2011) Functional properties of CD138- and CD138+ cells in multiple myeloma: study in the 5T33MM model. Haematologica 96(Suppl 1):34Google Scholar
  152. Wall DS, Wallace VA (2009) Hedgehog to Hes1: the heist of a Notch target. Cell Cycle 8:1301–1302PubMedGoogle Scholar
  153. Wang Z, Li Y, Banerjee S et al (2010) Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J Cell Biochem 109:726–736PubMedGoogle Scholar
  154. Weber JM, Calvi LM (2010) Notch signaling and the bone marrow hematopoietic stem cell niche. Bone 46:281–285PubMedGoogle Scholar
  155. Weng AP, Millholland JM, Yashiro-Ohtani Y et al (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–2109PubMedGoogle Scholar
  156. Wharton KA, Johansen KM, Xu T et al (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43:567–581PubMedGoogle Scholar
  157. Wilson JJ, Kovall RA (2006) Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA. Cell 124:985–996PubMedGoogle Scholar
  158. Wong GT, Manfra D, Poulet FM et al (2004) 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 279:12876–12882PubMedGoogle Scholar
  159. Wu F, Stutzman A, Mo YY (2007) Notch signaling and its role in breast cancer. Front Biosci 12:4370–4383PubMedGoogle Scholar
  160. Xu D, Hu J, De Bruyne E et al (2010) Involvement of Dll1/Notch interaction in MM drug resistance, clonogenic growth and in vivo engraftment. Blood-ASH Annual Meet Abst 116:1223Google Scholar
  161. Xu D, Hu J, De Bruyne E et al (2011) Dll1/Notch interaction induces drug resistance to Bortezomib by two distinct mechanism in multiple myeloma. Haematologica 96(s1):s36–37Google Scholar
  162. Xu D, Hu J, Xu S et al (2012a) Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM cell proliferation. Leukemia 26:1402–1405Google Scholar
  163. Xu D, Hu J, De Bruyne E et al (2012b) Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. Biochem Biophys Res Commun (in press)Google Scholar
  164. Yamada T, Yamazaki H, Yamane T et al (2003) Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells. Blood 101:2227–2234PubMedGoogle Scholar
  165. Yamamoto N, Yamamoto S, Inagaki F et al (2001) Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor. J Biol Chem 276:45031–45040PubMedGoogle Scholar
  166. Yan B, Raben N, Plotz P (2002) The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway. J Biol Chem 277:29760–29764PubMedGoogle Scholar
  167. Yin L (2005) Chondroitin synthase 1 is a key molecule in myeloma cell-osteoclast interactions. J Biol Chem 280:15666–15672PubMedGoogle Scholar
  168. Zanotti S, Canalis E (2010) Notch and the skeleton. Mol Cell Biol 30:886–896PubMedGoogle Scholar
  169. Zanotti S, Smerdel-Ramoya A, Stadmeyer L et al (2008) Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology 149:3890–3899PubMedGoogle Scholar
  170. Zhang XP, Zheng G, Zou L et al (2008) Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells. Mol Cell Biochem 307:101–108PubMedGoogle Scholar
  171. Zhao G, Liu Z, Ilagan MX et al (2010) Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin. J Neurosci 30:1648–1656PubMedGoogle Scholar
  172. Zweidler-McKay PA, He Y, Xu L et al (2005) Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 106:3898–3906PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Dehui Xu
    • 1
    • 2
  • Jinsong Hu
    • 1
    • 2
  • Elke De Bruyne
    • 1
  • Eline Menu
    • 1
  • Karin Vanderkerken
    • 1
  • Els Van Valckenborgh
    • 1
  1. 1.Department of Hematology and Immunology-Myeloma Center BrusselsVrije Universiteit Brussel (VUB)BrusselsBelgium
  2. 2.Department of Molecular Biology and GeneticsMedical School of Xi’an Jiaotong UniversityXi’anChina

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