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:

Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia

Leukemia volume 23, pages 393–396 (2009)Cite this article

Hematopoietic stem cell fate has been largely associated with a regulatory environment commonly referred to as niche.1 It remains unclear whether this microenvironment in the bone marrow is located in the endosteal region, the perivasculature or both.2 Nevertheless, direct cell–cell contact, soluble factors and extracellular matrix components have been implicated in the support of hematopoietic stem cells. Interestingly, most of these regulatory signals have also been associated with regulating the fate of leukemic cells. Among these, the chemokine CXCL12, also called stromal derived factor 1α (SDF-1α), expressed by marrow stromal cells and osteoblasts is essential for both homing and retention of hematopoietic stem cell in the bone marrow.3 Most importantly, Tavor and colleagues demonstrated using a transplant model in immunodeficient NOD/SCID/B2mnull mice that the motility of human acute myeloid leukemia (AML) cells relies on the SDF-1/CXCR4 axis.4

Preclinical experiments suggest that the interaction of leukemic blasts with bone marrow components may protect cells against chemotherapy.5, 6, 7 Using a murine model of minimal residual disease, Matsunaga et al. showed that the combination of the cytotoxic drug cytosine arabinoside with a blocking antibody against integrin α4 (VLA-4) increases significantly the survival rate of mice as compared with those treated with arabinoside only.8 More recently, Jin et al. reported that targeting the hyaluronic acid receptor CD44 eradicates leukemic stem cells in a murine serial transplantation model.9 Both reports suggest that the disruption of the interaction of leukemic cells and their bone marrow microenvironment is of primary importance for the effects observed in these animal studies. Nevertheless, to our knowledge no clinical data in humans supports this hypothesis. Here we report our first clinical experience with an AML patient treated with the CXCR4 antagonist AMD3100 within a compassionate use program in combination with standard chemotherapy.

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

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
Figure 2

References

  1. Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93–106.

    Article  CAS  Google Scholar 

  2. Kiel MJ, Morrison SJ . Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 2008; 8: 290–301.

    Article  CAS  Google Scholar 

  3. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID Mice on CXCR4. Science 1999; 283: 845–848.

    Article  CAS  Google Scholar 

  4. Tavor S, Petit I, Porozov S, Avigdor A, Dar A, Leider-Trejo L et al. CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice. Cancer Res 2004; 64: 2817–2824.

    Article  CAS  Google Scholar 

  5. Garrido SM, Appelbaum FR, Willman CL, Banker DE . Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Experimental Hematology 2001; 29: 448–457.

    Article  CAS  Google Scholar 

  6. Mudry RE, Fortney JE, York T, Hall BM, Gibson LF . Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 2000; 96: 1926–1932.

    CAS  PubMed  Google Scholar 

  7. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007; 67: 684–694.

    Article  CAS  Google Scholar 

  8. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A et al. Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 2003; 9: 1158–1165.

    Article  CAS  Google Scholar 

  9. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.

    Article  Google Scholar 

  10. Oelschlaegel U, Bornhauser M, Boxberger S, Kroschinsky F, Illmer T, Hoelig K et al. Kinetics of CXCR-4 and adhesion molecule expression during autologous stem cell mobilisation with G-CSF plus AMD3100 in patients with multiple myeloma. Annals of Hematology 2007; 86: 569–573.

    Article  CAS  Google Scholar 

  11. Zeng Z, Samudio IJ, Munsell M, An J, Huang Z, Estey E et al. Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias. Mol Cancer Ther 2006; 5: 3113–3121.

    Article  CAS  Google Scholar 

  12. Liesveld JL, Bechelli J, Rosell K, Lu C, Bridger G, Phillips II G et al. Effects of AMD3100 on transmigration and survival of acute myelogenous leukemia cells. Leukemia Research 2007; 31: 1553–1563.

    Article  CAS  Google Scholar 

  13. Juarez J, Bradstock KF, Gottlieb DJ, Bendall LJ . Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia 2003; 17: 1294–1300.

    Article  CAS  Google Scholar 

  14. Nervi B, Holt M, Rettig MP, Bridger G, Ley TJ, DiPersio JF . AMD3100 mobilizes acute promyelocytic leukemia cells from the bone marrow into the peripheral blood and sensitizes leukemia cells to chemotherapy. Blood 2005; 106 (Suppl.1): 246a.

    Google Scholar 

  15. Fukuda S, Pelus LM . Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1[alpha] but negatively regulates marrow homing in vivo. Experimental Hematology 2006; 34: 1041–1051.

    Article  CAS  Google Scholar 

  16. Rombouts EJC, Pavic B, Lowenberg B, Ploemacher RE . Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004; 104: 550–557.

    Article  CAS  Google Scholar 

  17. Jacobi A, Ryser MF, Koch S, Lehmann R, Bornhauser M, Brenner S . Interplay of CXCR4 and FLT3-ITD in the regulation of stem cell migration and proliferation. Blood 2007; 110 (Suppl. 1): 1818a.

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by the ‘Deutsche Forschungsgemeinschaft’ (SFB 655 to SB, GE and MB). Many thanks to the nursing staff and the physicians of the stem cell transplantation unit for the excellent patient care.

Author information

Authors and Affiliations

  1. Med Klinik und Poliklinik I, University Hospital, Dresden, Germany

    F A Fierro, U Oelschlaegel, G Ehninger, T Illmer & M Bornhäuser

  2. Department of Pediatrics, University Hospital, Dresden, Germany

    S Brenner & A Jacobi

  3. Pharmacy of the University Hospital, Dresden, Germany

    H Knoth

Authors
  1. F A Fierro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U Oelschlaegel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Jacobi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Knoth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Ehninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Illmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Bornhäuser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Bornhäuser.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fierro, F., Brenner, S., Oelschlaegel, U. et al. Combining SDF-1/CXCR4 antagonism and chemotherapy in relapsed acute myeloid leukemia. Leukemia 23, 393–396 (2009). https://doi.org/10.1038/leu.2008.182

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.182

This article is cited by

Search

Advanced search

Quick links