Skip to main content
SpringerLink
Log in

VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Very late antigen-4 (VLA-4) and CXC chemokine receptor 4 (CXCR4) perform critical roles in the adhesion of hematopoietic and leukemic stem cells to marrow stromal cells. This mechanism is associated with chemoresistance in patients with acute myeloid leukemia (AML). Here, we measured VLA-4 and CXCR4 expressions in leukemic myeloblasts to determine their prognostic implications. Using multicolor flow cytometry, positive VLA-4 and CXCR4 expressions were measured in leukemic myeloblasts in bone marrow aspirates that were obtained from newly diagnosed adult AML patients (n = 98). VLA-4 expression was higher in patients at favorable or intermediate cytogenetic risk than in patients at poor risk (p < 0.001 and p = 0.002, respectively), but CXCR4 expression was not significantly different. Among the 72 non-promyelocytic leukemia patients analyzed who received cytarabine + anthracycline-based induction chemotherapy, high VLA-4 expression was independently associated with a high probability of complete remission (p = 0.019) and superior relapse-free survival (RFS) (p < 0.001). However, high CXCR4 expression independently increased the probability of relapse (p = 0.002) and was associated with a shorter RFS (p = 0.006). When categorizing patients into three groups according to VLA-4 and CXCR4 expression levels, the group of high VLA-4 and low CXCR4 showed longer RFS (p = 0.001) and overall survival (OS) (p = 0.011) than the group of low VLA-4 or high CXCR4.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, Akiyama T, Kuroda H, Kawano Y, Kobune M, Kato J, Hirayama Y, Sakamaki S, Kohda K, Miyake K, Niitsu Y (2003) Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. Nat Med 9(9):1158–1165. doi:10.1038/nm909

    Article  CAS  PubMed  Google Scholar 

  2. Burger JA, Spoo A, Dwenger A, Burger M, Behringer D (2003) CXCR4 chemokine receptors (CD184) and alpha4beta1 integrins mediate spontaneous migration of human CD34+ progenitors and acute myeloid leukaemia cells beneath marrow stromal cells (pseudoemperipolesis). Br J Haematol 122(4):579–589

    Article  CAS  PubMed  Google Scholar 

  3. Nie Y, Han YC, Zou YR (2008) CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med 205(4):777–783. doi:10.1084/jem.20072513

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, Kulkarni S, Abboud CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, DiPersio JF (2012) A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood 119(17):3917–3924. doi:10.1182/blood-2011-10-383406

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Matsunaga T, Fukai F, Miura S, Nakane Y, Owaki T, Kodama H, Tanaka M, Nagaya T, Takimoto R, Takayama T, Niitsu Y (2008) Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia 22(2):353–360. doi:10.1038/sj.leu.2405017

    Article  CAS  PubMed  Google Scholar 

  6. Spoo AC, Lubbert M, Wierda WG, Burger JA (2007) CXCR4 is a prognostic marker in acute myelogenous leukemia. Blood 109(2):786–791. doi:10.1182/blood-2006-05-024844

    Article  CAS  PubMed  Google Scholar 

  7. Tavernier-Tardy E, Cornillon J, Campos L, Flandrin P, Duval A, Nadal N, Guyotat D (2009) Prognostic value of CXCR4 and FAK expression in acute myelogenous leukemia. Leuk Res 33(6):764–768. doi:10.1016/j.leukres.2008.10.014

    Article  CAS  PubMed  Google Scholar 

  8. Rombouts EJ, Pavic B, Lowenberg B, Ploemacher RE (2004) Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 104(2):550–557. doi:10.1182/blood-2004-02-0566

    Article  CAS  PubMed  Google Scholar 

  9. Becker PS, Kopecky KJ, Wilks AN, Chien S, Harlan JM, Willman CL, Petersdorf SH, Stirewalt DL, Papayannopoulou T, Appelbaum FR (2009) Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia. Blood 113(4):866–874. doi:10.1182/blood-2007-12-124818

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Walter RB, Alonzo TA, Gerbing RB, Ho PA, Smith FO, Raimondi SC, Hirsch BA, Gamis AS, Franklin JL, Hurwitz CA, Loken MR, Meshinchi S (2010) High expression of the very late antigen-4 integrin independently predicts reduced risk of relapse and improved outcome in pediatric acute myeloid leukemia: a report from the children’s oncology group. J Clin Oncol 28(17):2831–2838. doi:10.1200/JCO.2009.27.5693

    Article  PubMed Central  PubMed  Google Scholar 

  11. Bendall LJ, Kortlepel K, Gottlieb DJ (1993) Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms. Blood 82(10):3125–3132

    CAS  PubMed  Google Scholar 

  12. Burger JA, Burger M, Kipps TJ (1999) Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood 94(11):3658–3667

    CAS  PubMed  Google Scholar 

  13. Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647. doi:10.1146/annurev.immunol.25.022106.141618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Sudhoff T, Wehmeier A, Kliche KO, Aul C, Schlomer P, Bauser U, Schneider W (1996) Levels of circulating endothelial adhesion molecules (sE-selectin and sVCAM-1) in adult patients with acute leukemia. Leukemia 10(4):682–686

    CAS  PubMed  Google Scholar 

  15. Pankov R, Yamada KM (2002) Fibronectin at a glance. J Cell Sci 115(Pt 20):3861–3863

    Article  CAS  PubMed  Google Scholar 

  16. Solanilla A, Grosset C, Duchez P, Legembre P, Pitard V, Dupouy M, Belloc F, Viallard JF, Reiffers J, Boiron JM, Coulombel L, Ripoche J (2003) Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism. Br J Haematol 120(5):782–786

    Article  CAS  PubMed  Google Scholar 

  17. Lataillade JJ, Clay D, Dupuy C, Rigal S, Jasmin C, Bourin P, Le Bousse-Kerdiles MC (2000) Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood 95(3):756–768

    CAS  PubMed  Google Scholar 

  18. Devine SM, Flomenberg N, Vesole DH, Liesveld J, Weisdorf D, Badel K, Calandra G, DiPersio JF (2004) Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin’s lymphoma. J Clin Oncol 22(6):1095–1102. doi:10.1200/JCO.2004.07.131

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant from the Asan Institute for Life Science (2010-109).

Authorship

C-JP and K-HL designed and conducted the research. MHB collected, analyzed, and interpreted data; performed statistical analysis; and wrote the manuscript. S-HO collected, analyzed, and interpreted data. B-RL performed flow cytometric experiments. SHP performed morphologic analysis and molecular analysis. YJK, Y-UC, and SJ performed morphologic analysis. J-H Lee and K-HL managed patients, provided clinical data, and are involved in prognostic analysis. NK performed and analyzed flow cytometric data. J-H Lim and E-JS performed chromosomal analysis.

C-JP and K-HL contributed equally to this study, having full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of interest

The authors have no conflicts of interest to report.

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Mi Hyun Bae, Sung-Hee Oh, Chan-Jeoung Park, Bo-Ra Lee, Young Jin Kim, Young-Uk Cho, Seongsoo Jang, Ji-Hun Lim & Eul-Ju Seo

  2. Department of Internal Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea

    Je-Hwan Lee & Kyoo-Hyung Lee

  3. Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea

    Nayoung Kim

  4. Department of Laboratory Medicine, Pusan National University School of Medicine, Pusan National University Hospital, Busan, Korea

    Sang Hyuk Park

Authors
  1. Mi Hyun Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sung-Hee Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chan-Jeoung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bo-Ra Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Young-Uk Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seongsoo Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Je-Hwan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nayoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Sang Hyuk Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ji-Hun Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Eul-Ju Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kyoo-Hyung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Chan-Jeoung Park or Kyoo-Hyung Lee.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOC 3.01 mb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bae, M.H., Oh, SH., Park, CJ. et al. VLA-4 and CXCR4 expression levels show contrasting prognostic impact (favorable and unfavorable, respectively) in acute myeloid leukemia. Ann Hematol 94, 1631–1638 (2015). https://doi.org/10.1007/s00277-015-2442-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-015-2442-8

Keywords

Search

Navigation