Survival and Proliferation Factors of Normal and Malignant Plasma Cells

  • Bernard Klein
  • Karin Tarte
  • Michel Jourdan
  • Karene Mathouk
  • Jerome Moreaux
  • Eric Jourdan
  • Eric Legouffe
  • John De Vos
  • Jean François Rossic
Article

Abstract

Since the first identification of interleukin (IL)-6 as a myeloma cell growth factor by Dr. Kawano’s and Dr. Klein’s groups 14 years ago, numerous studies have emphasized its major roles in the emergence of malignant plasma cells in vivo and in the generation of normal plasma cells. Four transcription factors control B-cell differentiation into plasma cells. The B-cell transcription factor pax-5 is mainly responsible for a B-cell phenotype, andbcl-6 represses the plasma cell transcription factor blimp-1 and plasma cell differentiation.bcl-6 expression is triggered by CD40 and IL-4 activation. A lack of CD40 and IL-4 activation yields a down-regulation ofbcl-6 expression, and IL-6 stimulation yields an up-regulation of blimp-1, mainly through STAT3 activation. Blimp-1 further down-regulatesbcl-6 andpax-5 expression and makes plasma cell differentiation possible. IL-6 as well as IL-10 up-regulate XBP-1. XBP-1 is another transcription factor that is involved in plasma cell differentiation and whose gene expression is shut down by pax-5.The plasma cell transcription factors blimp-1 and XBP-1 are up-regulated, and the B-cell transcription factors bcl-6 and pax-5 are down-regulated, in malignant cells compared to B-cells. Apart from the recent identification of these 4 transcription factors, the factors involved in normal plasma cell generation are mostly unknown. Regarding malignant plasma cells, 3 categories of growth factors have been identified: (1) the IL-6 family cytokines, IL-10, and interferon α that activate the Janus kinase—signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase pathways; (2) growth factors activating the phosphatidylinositol (PI)-3 kinase/AKT and MAP kinase pathways, unlike the JAK/STAT pathway (insulin-like growth factor 1, hepatocyte growth factor, and members of the epidermal growth factor family able to bind syndecan-1 proteoglycan); and (3) B-cell—activating factor (BAFF) or proliferationinducing ligand (APRIL) that activate the nuclear factor κB and PI-3 kinase/AKT pathways.BAFF and APRIL bind to BAFF receptor and TACI and are major B-cell survival factors. Recent data indicate that these various growth factors may cooperate to provide optimum signaling because they are localized together and with cytoplasmic transduction elements in caveolinlinked membrane caveolae. The identification of these myeloma cell growth factors and of the associated transduction pathways should provide novel therapeutic targets in multiple myeloma.

Key words

Myeloma IL-6 IGF-1 HGF EGF BAFF 

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Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • Bernard Klein
    • 1
  • Karin Tarte
    • 1
  • Michel Jourdan
    • 1
  • Karene Mathouk
    • 1
  • Jerome Moreaux
    • 1
  • Eric Jourdan
    • 2
  • Eric Legouffe
    • 3
  • John De Vos
    • 1
  • Jean François Rossic
    • 1
  1. 1.INSERM U475 and Unit for Cellular and Gene TherapyMontpellierFrance
  2. 2.Service de Médecine Interne BCHU de Nîmes, Nîmes
  3. 3.Service d’Hématologie et Oncologie MédicaleCHU Montpellier, Hôspital LapeyronieMontpellierFrance

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