Advertisement

International Journal of Hematology

, Volume 75, Issue 5, pp 508–513 | Cite as

Activation of Extracellular Signal-Regulated Kinase through B-Cell Antigen Receptor in B-Cell Chronic Lymphocytic Leukemia

  • Kiyotaka Kawauchi
  • Toshie Ogasawara
  • Masako Yasuyama
Case Report

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) cells express on their surface membranes immunoglobulin (Ig) M or IgD, both of which normally function as B-cell antigen receptors (BCRs). However, in contrast to normal B-cells, in B-CLL cells several important signaling pathways, such as the activation of protein tyrosine kinase via BCR, are defective. We have examined whether the activities of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38 MAPK, and Akt kinase, are functional in B-CLL cells, because these kinases play critical roles in activation in response to BCR stimulation, tumor cell growth, and survival. In B-CLL cells, BCR cross-linking neither induced activation nor enhanced the activities of Lyn, Syk, p21ras, JNK, p38 MAPK, or Akt kinases, whereas p38 MAPK and Akt were constitutively active. In contrast, BCR cross-linking resulted in ERK activation, although the activation in quiescent cells was case dependent.These results suggest that some signaling pathways, such as the activation of ERK through BCR, are functional in B-CLL cells despite the extensive impairment of signaling pathways.

Key words

B-CLL MAPK B-cell antigen receptor 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Kurosaki T. Genetic analysis of B cell antigen receptor signaling.Annu Rev Immunol. 1999;17:555–592.CrossRefGoogle Scholar
  2. 2.
    Chang L, Karin M. Mammalian MAP kinase signalling cascades.Nature. 2001;410:37–40.CrossRefGoogle Scholar
  3. 3.
    Stambolic V, Mak TW, Woodgett JR. Modulation of cellular apoptotic potential: contributions to oncogenesis.Oncogene. 1999;18: 6094–6103.CrossRefPubMedGoogle Scholar
  4. 4.
    Lankester AC, van Schijndel GMW, vander Schoot CE, van Oers MHJ, van Noesel CJM, van Lier RAW. Antigen receptor nonre-sponsiveness in chronic lymphocytic leukemia B cells.Blood. 1995; 86:1090–1097.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Semichon M, Merle-Beral H, Lang V, Bismuth G. Normal Syk protein level but abnormal tyrosine phosphorylation in B-CLL cells.Leukemia 1997;11:1921–1928.CrossRefPubMedGoogle Scholar
  6. 6.
    Hivroz C, Grillot-Courvalin C, Brouet JC, Seligmann M. Heterogeneity of responsiveness of chronic lymphocytic leukemic B cells to B cell growth factor or interleukin 2.Eur J Immunol. 1986;16: 1001–1007.CrossRefPubMedGoogle Scholar
  7. 7.
    Zupo S, Massara R, Dono M., et al. Apoptosis or plasma cell differentiation of CD38-positive B-chronic lymphocytic leukemia cells induced by cross-linking of surface IgM or IgD.Blood. 2000;95: 1199–1206.PubMedGoogle Scholar
  8. 8.
    Gold MR, Law DA, DeFranco AL. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor.Nature.1990;345:810–813.CrossRefPubMedGoogle Scholar
  9. 9.
    Melamed I, Wang G, Roifman CM. Antigen receptor-mediated protein tyrosine kinase activity is regulated by a pertussis toxin-sensitive G protein.J Immunol. 1992;149:169–174.PubMedGoogle Scholar
  10. 10.
    Kawauchi K, Lazarus AH, Rapoport MJ, Harwood A, Cambier JC, Delovitch TL. Tyrosine kinase and CD45 tyrosine phosphatase activity mediate Ras activation in B cells stimulated through the antigen receptor.J Immunol. 1994;152:3306–3316.PubMedGoogle Scholar
  11. 11.
    Whalen AM, Galasinski SC, Shapiro PS, Nahreini TS, Ahn NG. Megakaryocytic differentiation induced by constitutive activation of mitogen-activated protein kinase kinase.Mol Cell Biol. 1997;17: 1947–1958.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.Nature. 1997;385: 169–172.CrossRefPubMedGoogle Scholar
  13. 13.
    Deckert M, Tartare-Deckert S, Couture C, Mustelin T, Altman A. Functional and physical interactions of Syk-family kinases with the Vav protooncogene product.Immunity. 1996;5:591–604.CrossRefPubMedGoogle Scholar
  14. 14.
    Kolch W. Meaningful relationships: the regulation of the Ras/Raf/ MEK/ERK pathway by protein interactions.Biochem J. 2000;351: 289–305.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Reed JC. Molecular biology of chronic lymphocytic leukemia.Semin Oncol. 1998;25:11–18.PubMedGoogle Scholar
  16. 16.
    Nagata Y, Takahashi N, Davis RJ, Todokoro K. Activation of p38 MAP kinase and JNK but not ERK is required for erythropoietin-induced erythroid differentiation.Blood. 1998;92:1859–1869.Google Scholar
  17. 17.
    Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T. BCAP: the tyrosine kinase substrate that connects B cell receptor to phospho-inositide 3-kinase activation.Immunity. 2000;13:817–827.CrossRefPubMedGoogle Scholar
  18. 18.
    Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis.Blood Cells Mol Dis. 2000;26:133–143.CrossRefPubMedGoogle Scholar
  19. 19.
    Wilkinson MG, Millar JBA. Control of eukaryotic cell cycle by MAP kinase signaling pathways.FASEB J. 2000;14:2147–2157.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2002

Authors and Affiliations

  • Kiyotaka Kawauchi
    • 1
  • Toshie Ogasawara
    • 1
  • Masako Yasuyama
    • 1
  1. 1.Department of MedicineTokyo Women’s Medical University Daini HospitalTokyoJapan

Personalised recommendations