International Journal of Hematology

, Volume 78, Issue 2, pp 121–125 | Cite as

Recent Advances in Understanding the Pathogenesis of Anemia in Multiple Myeloma

  • Franco Silvestris
  • Marco Tucci
  • Cosima Quatraro
  • Franco Dammacco


Anemia is a prominent feature of multiple myeloma (MM) and is commonly associated with clinical progression of MM. In addition to being affected by a number of pathogenetic events, including imbalance of the cytokine network, inappropriate erythropoietin (EPO) levels, blood loss, and hemolysis, the erythroid matrix is chronically deteriorated by the malignant plasma cell clone that activates a cytotoxic mechanism directed at the erythroid progenitors. In particular, malignant plasma cells express very high levels of apoptogenic receptors, including both Fas ligand and tumor necrosis factor-related apoptosisinducing ligand, which trigger apoptosis of immature erythroblasts by stimulating specific death receptors, namely Fas and the complex DR4/DR5. Erythroid cells also weakly express the transcription factor GATA-1, which drives erythroblast maturation by inhibiting apoptosis through antiapoptotic molecules such as EPO and Bcl-xL. This newly discovered pathogenetic mechanism of anemia in MM is based on persistent erythroblast cytotoxicity within the bone marrow that leads to progressive destruction of the erythroid matrix.

Key words

Anemia Erythroblast apoptosis Fas-L Multiple myeloma TRAIL 


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  1. 1.
    Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease.Blood. 1992;80:1639–1647.PubMedGoogle Scholar
  2. 2.
    MacLennan IC, Drayson M, Dunn J. Multiple myeloma.Br Med J. 1994;308:1033–1036.CrossRefGoogle Scholar
  3. 3.
    Merico F, Bergui L, Gregoretti MG, et al. Cytokines involved in the progression of multiple myeloma.Clin Exp Immunol. 1993;921:27–31.Google Scholar
  4. 4.
    Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease.Blood. 2002;100:3776–3781.CrossRefPubMedGoogle Scholar
  5. 5.
    Carson DA, Ribeiro JM. Apoptosis and disease.Lancet. 1993;341:1251–1254.CrossRefPubMedGoogle Scholar
  6. 6.
    Ameisen JC. Programmed cell death (apoptosis) and AIDS pathogenesis.AIDS Res Hum Retroviruses. 1994;10(suppl 1):S3-S5.PubMedGoogle Scholar
  7. 7.
    Loken MR, Civin CI, Bigbee WL, Langlois RG, Jensen RH. Coordinate glycosylation and cell surface expression of glycophorin A during normal human erythropoiesis.Blood. 1987;70:1959–1961.PubMedGoogle Scholar
  8. 8.
    De Maria R, Testa U, Luchetti L, et al. Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis.Blood. 1999;93:796–803.PubMedGoogle Scholar
  9. 9.
    Zamai L, Secchiero P, Pierpaoli S, et al. TNF-related apoptosisinducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis.Blood. 2000;95:3716–3724.PubMedGoogle Scholar
  10. 10.
    Park JR. Cytokine regulation of apoptosis in hematopoietic precursor cells.Curr Opin Hematol. 1996;3:191–196.CrossRefPubMedGoogle Scholar
  11. 11.
    Denizot Y, Fixe P, Liozon E, Praloran V. Serum interleukin-8 (IL-8) and IL-6 concentrations in patients with hematologic malignancies.Blood. 1996;87:4016–4017.PubMedGoogle Scholar
  12. 12.
    Francia di Celle P, Mariani S, Riera L, Stacchini A, Reato G, Foa R. Interleukin-8 induces the accumulation of B-cell chronic lymphocytic leukemia cells by prolonging survival in an autocrine fashion.Blood. 1996;87:4382–4389.Google Scholar
  13. 13.
    Hermouet S, Godard A, Pineau D, et al. Abnormal production of interleukin (IL)-11 and IL-8 in polycythaemia vera.Cytokine. 2002;20:178–183.CrossRefPubMedGoogle Scholar
  14. 14.
    De Maria R, Zeuner A, Eramo A, et al. Negative regulation of erythropoiesis by caspase-mediated cleavage of GATA-1.Nature. 1999;401:489–493.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zermati Y, Garrido C, Amsellem S, et al. Caspase activation is required for terminal erythroid differentiation.J Exp Med. 2001;193:247–254.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Morioka K, Tone S, Mukaida M, Takano-Ohmuro H. The apoptotic and nonapoptotic nature of the terminal differentiation of erythroid cells.Exp Cell Res. 1998;240:206–217.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sahara S, Aoto M, Eguchi Y, Imamoto N, Yoneda Y, Tsujimoto Y. Acinus is a caspase-3—activated protein required for apoptotic chromatin condensation.Nature. 1999;401:168–173.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Frassanito MA, Silvestris F, Silvestris N, et al. Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells.Clin Exp Immunol. 1998;114:179–188.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Geissler K, Ohler L, Fodinger M, et al. Interleukin-10 inhibits erythropoietin-independent growth of erythroid bursts in patients with polycythemia vera.Blood. 1998;92:1967–1972.PubMedGoogle Scholar
  20. 20.
    Shima Y, Nishimoto N, Ogata A, Fujii Y, Yoshizaki K, Kishimoto T. Myeloma cells express Fas antigen/APO-1 (CD95) but only some are sensitive to anti-Fas antibody resulting in apoptosis.Blood. 1995;85:757–764.PubMedGoogle Scholar
  21. 21.
    Westendorf JJ, Lammert JM, Jelinek DF. Expression and function of Fas (APO-1/CD95) in patient myeloma cells and myeloma cell lines.Blood. 1995;85:3566–3576.PubMedGoogle Scholar
  22. 22.
    Villunger A, Egle A, Marschitz I, et al. Constitutive expression of Fas (Apo-1/CD95) ligand on multiple myeloma cells: a potential mechanism of tumor-induced suppression of immune surveillance.Blood. 1997;90:12–20.PubMedGoogle Scholar
  23. 23.
    Cheng J, Zhou T, Liu C, et al. Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule.Science. 1994;263:1759–1762.CrossRefPubMedGoogle Scholar
  24. 24.
    Silvestris F, Tucci M, Cafforio P, Dammacco F. Fas-L up-regulation by highly malignant myeloma plasma cells: role in the pathogenesis of anemia and disease progression.Blood. 2001;97:1155–1164.CrossRefPubMedGoogle Scholar
  25. 25.
    Silvestris F, Cafforio P, Tucci M, Dammacco F. Negative regulation of erythroblast maturation by Fas-L(+)/TRAIL(+) highly malignant plasma cells: a major pathogenetic mechanism of anemia in multiple myeloma.Blood. 2002;99:1305–1313.CrossRefPubMedGoogle Scholar
  26. 26.
    Bataille R, Harousseau JL. Multiple myeloma.N Engl J Med. 1997;336:1657–1664.CrossRefPubMedGoogle Scholar
  27. 27.
    Ameisen, JC. Programmed cell death (apoptosis) and cell survival regulation: relevance to AIDS and cancer.AIDS. 1994;8:1197–1213.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  • Franco Silvestris
    • 1
  • Marco Tucci
    • 1
  • Cosima Quatraro
    • 1
  • Franco Dammacco
    • 1
  1. 1.DIMO, Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical OncologyUniversity of BariBariItaly

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