Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Reduced CXCR4 expression is associated with extramedullary disease in a mouse model of myeloma and predicts poor survival in multiple myeloma patients treated with bortezomib

Leukemia volume 27, pages 2075–2077 (2013)Cite this article

Subjects

Drug resistance to the proteasome inhibitor, bortezomib/VELCADE (Bz) is a significant clinical problem in the treatment of multiple myeloma (MM), an invariably fatal plasma cell malignancy of the bone marrow.1 Despite initial success and wide use in cocktail regimens for MM treatment,2 the majority of patients treated with Bz eventually relapse, many having developed ‘acquired’ Bz-resistant (BzR) disease.1 Thus, the elucidation of mechanisms by which Bz resistance may occur and the identification of novel intervention strategies are important translational aims.

To identify mechanisms of acquired Bz resistance, we previously utilized in vitro cell lines from the Bcl-XL/Myc mouse model of plasma cell malignancy to systematically ascertain differences between Bz-sensitive (BzS) and derived BzR cells.3 We have employed this model system because malignant plasma cell lines isolated from these mice closely resemble human MM based on gene expression, chromosomal abnormalities and progression of disease in the bone marrow.3, 4, 5 Perhaps most importantly, from initially drug-sensitive tumor cell populations we are able to select for drug-resistant cells in vitro, adoptively transfer these cells back into syngeneic recipient mice, and recapitulate the drug-sensitive or -resistant phenotype following in vivo Bz treatment of recipient mice.3 Remarkably, the differences in Bz sensitivity in our mouse cell lines strongly correlated with differences in malignant plasma cell migration following adoptive transfer. BzR cells displayed a significantly reduced affinity for the bone marrow compartment, compared with their sensitive counterparts, and instead infiltrated extramedullary tissues more readily,3 suggesting the possibility that BzR plasma cells (PCs) are more likely to reside outside of the bone marrow milieu. Thus, we hypothesized that Bz treatment and acquisition of resistance selects for cells that can survive independent of the bone marrow microenvironment and that this phenotype may be due to the loss of cell-surface proteins that mediate the MM–bone marrow stromal cell (BMSC) interaction.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: 2609–2617.

    Article  CAS  PubMed  Google Scholar 

  2. Shah JJ, Orlowski RZ . Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 2009; 23: 1964–1979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stessman HA, Baughn LB, Sarver A, Xia T, Deshpande R, Mansoor A et al. Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Mol Cancer Ther 2013; e-pub ahead of print 27 March 2013; doi:10.1158/1535-7163.MCT-12-1151.

  4. Cheung WC, Kim JS, Linden M, Peng L, Van Ness B, Polakiewicz RD et al. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice. J Clin Invest 2004; 113: 1763–1773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boylan KL, Gosse MA, Staggs SE, Janz S, Grindle S, Kansas GS et al. A transgenic mouse model of plasma cell malignancy shows phenotypic, cytogenetic, and gene expression heterogeneity similar to human multiple myeloma. Cancer Res 2007; 67: 4069–4078.

    Article  CAS  PubMed  Google Scholar 

  6. Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood 2007; 109: 2708–2717.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 2007; 109: 3177–3188.

    Article  CAS  PubMed  Google Scholar 

  8. Shaughnessy JD Jr, Qu P, Usmani S, Heuck CJ, Zhang Q, Zhou Y et al. Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with total therapy 3. Blood 2011; 118: 3512–3524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Usmani SZ, Crowley J, Hoering A, Mitchell A, Waheed S, Nair B et al. Improvement in long-term outcomes with successive Total Therapy trials for multiple myeloma: are patients now being cured? Leukemia 2013; 27: 226–232.

    Article  CAS  PubMed  Google Scholar 

  10. Kunkel EJ, Butcher EC . Plasma-cell homing. Nat Rev Immunol 2003; 3: 822–829.

    Article  CAS  PubMed  Google Scholar 

  11. Azab AK, Runnels JM, Pitsillides C, Moreau AS, Azab F, Leleu X et al. CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy. Blood 2009; 113: 4341–4351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moriuchi M, Ohmachi K, Kojima M, Tsuboi K, Ogawa Y, Nakamura N et al. Three cases of bortezomib-resistant multiple myeloma with extramedullary masses. Tokai J Exp Clin Med 2010; 35: 17–20.

    CAS  PubMed  Google Scholar 

  13. Peceliunas V, Janiulioniene A, Matuzeviciene R, Zvirblis T, Griskevicius L . Circulating plasma cells predict the outcome of relapsed or refractory multiple myeloma. Leuk Lymphoma 2012; 53: 641–647.

    Article  CAS  PubMed  Google Scholar 

  14. Mo SL, Li J, Loh YS, Brown RD, Smith AL, Chen Y et al. Factors influencing the abundance of the side population in a human myeloma cell line. Bone Marrow Res 2011; 2011: 524845.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA

    H A F Stessman, A Mansoor, L B Baughn & B Van Ness

  2. Department of Masonic Cancer Center Bioinformatics Support and Services, University of Minnesota, Minneapolis, MN, USA

    F Zhan

  3. Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Marrow Transplantation, Iowa City, IA, USA

    F Zhan

  4. Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA

    S Janz

  5. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USAE-mail: vanne001@umn.edu,

    M A Linden & L B Baughn

Authors
  1. H A F Stessman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Mansoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Janz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M A Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L B Baughn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B Van Ness
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to L B Baughn or B Van Ness.

Ethics declarations

Competing interests

BVN receives research support from Millennium Pharmaceuticals Inc., Cambridge, MA. The other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stessman, H., Mansoor, A., Zhan, F. et al. Reduced CXCR4 expression is associated with extramedullary disease in a mouse model of myeloma and predicts poor survival in multiple myeloma patients treated with bortezomib. Leukemia 27, 2075–2077 (2013). https://doi.org/10.1038/leu.2013.148

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2013.148

This article is cited by

Search

Advanced search

Quick links