VLA-4: A Cell’s Consequential Encounter

  • Thalia PapayannopoulouEmail author
Part of the Current Cancer Research book series (CUCR)


The role of integrins as modulators of hematopoietic cell function is continuously evolving. After the initial establishment of integrins as the primary forces necessary for adhesion and migration of mature leucocytes, new roles in hematopoietic stem/progenitor cell retention and/or function in bone marrow (BM) were uncovered; more recently, attention has shifted to neoplastic hematopoiesis and cancer with instrumental integrin-dependent influences on reciprocal interactions of neoplastic cells with their microenvironment. The ever-expanding knowledge of integrin-mediated signaling and their multitude of signaling mediators and other cooperating molecules provide ample opportunities for harnessing this multifaceted influence of integrins for therapeutic benefit. In this context, a brief account of very late antigen 4 (VLA4) integrin in normal and neoplastic hematopoiesis is presented.


Integrins VLA4 Mobilization Microenvironment Leukemia 


  1. Arroyo AG, Yang JT, Rayburn H, Hynes RO (1999) Alpha4 integrins regulate the proliferation/differentiation balance of multilineage hematopoietic progenitors in vivo. Immunity 11(5):555–566CrossRefPubMedGoogle Scholar
  2. Arroyo AG, Taverna D, Whittaker CA, Strauch UG, Bader BL, Rayburn H, Crowley D, Parker CM, Hynes RO (2000) In vivo roles of integrins during leukocyte development and traffic: insights from the analysis of mice chimeric for alpha 5, alpha v, and alpha 4 integrins. J Immunol 165(8):4667–4675CrossRefPubMedGoogle Scholar
  3. Barkan D, Chambers AF (2011) beta1-integrin: a potential therapeutic target in the battle against cancer recurrence. Clin Cancer Res 17(23):7219–7223. doi:10.1158/1078-0432.CCR-11-0642CrossRefPubMedGoogle Scholar
  4. 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-2007-12-124818CrossRefPubMedCentralPubMedGoogle Scholar
  5. Bhatia R, Wayner EA, McGlave PB, Verfaillie CM (1994) Interferon-alpha restores normal adhesion of chronic myelogenous leukemia hematopoietic progenitors to bone marrow stroma by correcting impaired beta 1 integrin receptor function. J Clin Invest 94(1):384–391. doi:10.1172/JCI117333CrossRefPubMedCentralPubMedGoogle Scholar
  6. Bhatia R, McGlave PB, Verfaillie CM (1995) Treatment of marrow stroma with interferon-alpha restores normal beta 1 integrin-dependent adhesion of chronic myelogenous leukemia hematopoietic progenitors. Role of MIP-1 alpha. J Clin Invest 96(2):931–939. doi:10.1172/JCI118141CrossRefPubMedCentralPubMedGoogle Scholar
  7. Bonig H, Watts KL, Chang KH, Kiem HP, Papayannopoulou T (2009) Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells 27(4):836–837. doi:10.1002/stem.9CrossRefPubMedCentralPubMedGoogle Scholar
  8. Brakebusch C, Fassler R (2005) beta 1 integrin function in vivo: adhesion, migration and more. Cancer Metastasis Rev 24(3):403–411. doi:10.1007/s10555-005-5132-5CrossRefPubMedGoogle Scholar
  9. Brakebusch C, Bouvard D, Stanchi F, Sakai T, Fassler R (2002a) Integrins in invasive growth. J Clin Invest 109(8):999–1006. doi:10.1172/JCI15468CrossRefPubMedCentralPubMedGoogle Scholar
  10. Brakebusch C, Fillatreau S, Potocnik AJ, Bungartz G, Wilhelm P, Svensson M, Kearney P, Korner H, Gray D, Fassler R (2002b) Beta1 integrin is not essential for hematopoiesis but is necessary for the T cell-dependent IgM antibody response. Immunity 16(3):465–477CrossRefPubMedGoogle Scholar
  11. Burger JA, Spoo A, Dwenger A, Burger M, Behringer D (2003) CXCR4 chemokine receptors (CD184) and α4β1 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. doi:10.1046/j.1365-2141.2003.04466.xCrossRefPubMedGoogle Scholar
  12. Chien S, Zhao X, Patton JT, Smith T, Sarkar A, Magnani JL, Appelbaum FR, Becker PS (2011) Novel dual E-selectin-CXCR4 Inhibitors Mobilize Human Acute Myeloid Leukemia (AML) cells in the NODscid IL2R{gamma}c-/- Xenograft and confer susceptibility to cytarabine. ASH Annual Meeting Abstracts 118(21):579Google Scholar
  13. Craddock CF, Nakamoto B, Andrews RG, Priestley GV, Papayannopoulou T (1997) Antibodies to VLA4 integrin mobilize long-term repopulating cells and augment cytokine-induced mobilization in primates and mice. Blood 90(12):4779–4788PubMedGoogle Scholar
  14. Etoh T, Byers HR, Mihm MC Jr (1992) Integrin expression in malignant melanoma and their role in cell attachment and migration on extracellular matrix proteins. J Dermatol 19(11):841–846PubMedGoogle Scholar
  15. Faull RJ, Kovach NL, Harlan JM, Ginsberg MH (1993) Affinity modulation of integrin alpha 5 beta 1: regulation of the functional response by soluble fibronectin. J Cell Biol 121(1):155–162. doi:10.1083/jcb.121.1.155CrossRefPubMedGoogle Scholar
  16. Guo-Bao W, Xiao-Qin C, Qi-Rong G, Jie L, Gui-Nan L, Yue L (2010) Arsenic Trioxide overcomes cell adhesion-mediated drug resistance through down-regulating the expression of beta(1)-integrin in K562 chronic myelogenous leukemia cell line. Leuk Lymphoma 51(6):1090–1097. doi:10.3109/10428191003746315CrossRefPubMedGoogle Scholar
  17. Hata H, Matsuzaki H, Matsuno F, Yoshida M, Sonoki T, Takemoto S, Takatsuki K (1993) Expression of fibronectin and adhesion to fibronectin in myeloma cell lines. Acta Haematol 89(1):26–31CrossRefPubMedGoogle Scholar
  18. Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T, Muroi K, Kano Y, Furukawa Y, Ozawa K (2008) Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 28(2):231–242. doi: CrossRefGoogle Scholar
  19. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69(1):11–25CrossRefPubMedGoogle Scholar
  20. Jiang Y, Zhao RC, Verfaillie CM (2000) Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. Proc Natl Acad Sci U S A 97(19):10538–10543. doi:10.1073/pnas.190104497CrossRefPubMedCentralPubMedGoogle Scholar
  21. Katayama Y, Hidalgo A, Furie BC, Vestweber D, Furie B, Frenette PS (2003) PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and alpha4 integrin. Blood 102(6):2060–2067. doi:10.1182/blood-2003-04-1212CrossRefPubMedGoogle Scholar
  22. Lane SW, Scadden DT, Gilliland DG (2009) The leukemic stem cell niche: current concepts and therapeutic opportunities. Blood 114(6):1150–1157. doi:10.1182/blood-2009-01-202606CrossRefPubMedCentralPubMedGoogle Scholar
  23. Legate KR, Wickstrom SA, Fassler R (2009) Genetic and cell biological analysis of integrin outside-in signaling. Genes Dev 23(4):397–418. doi:10.1101/gad.1758709CrossRefPubMedGoogle Scholar
  24. Luo B-H, Springer TA (2006) Integrin structures and conformational signaling. Curr Opin Cell Biol 18(5):579–586. doi:10.1016/ Scholar
  25. Majid A, Lin TT, Best G, Fishlock K, Hewamana S, Pratt G, Yallop D, Buggins AG, Wagner S, Kennedy BJ, Miall F, Hills R, Devereux S, Oscier DG, Dyer MJ, Fegan C, Pepper C (2011) CD49d is an independent prognostic marker that is associated with CXCR4 expression in CLL. Leukemia Res 35(6):750–756. doi:10.1016/j.leukres.2010.10.022CrossRefGoogle Scholar
  26. 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: CrossRefPubMedGoogle Scholar
  27. 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.2405017CrossRefPubMedGoogle Scholar
  28. Ngo HT, Leleu X, Lee J, Jia X, Melhem M, Runnels J, Moreau AS, Burwick N, Azab AK, Roccaro A, Azab F, Sacco A, Farag M, Sackstein R, Ghobrial IM (2008) SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. Blood 112(1):150–158. doi:10.1182/blood-2007-12-129395CrossRefPubMedCentralPubMedGoogle Scholar
  29. Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda M, Nobuyoshi M, Oh I, Sato K, Suzuki T, Ozaki K, Mori M, Nagai T, Muroi K, Kano Y, Furukawa Y, Ozawa K (2009) Bortezomib overcomes cell-adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 28(2):231–242. doi:10.1038/onc.2008.385CrossRefPubMedGoogle Scholar
  30. Nuckel H, Switala M, Collins CH, Sellmann L, Grosse-Wilde H, Duhrsen U, Rebmann V (2009) High CD49d protein and mRNA expression predicts poor outcome in chronic lymphocytic leukemia. Clin Immunol 131(3):472–480. doi:10.1016/j.clim.2009.02.004CrossRefPubMedGoogle Scholar
  31. Papayannopoulou T (2003) Bone marrow homing: the players, the playfield, and their evolving roles. Curr Opin Hematol 10(3):214–219CrossRefPubMedGoogle Scholar
  32. Papayannopoulou T (2004) Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103(5):1580–1585. doi:10.1182/blood-2003-05-1595CrossRefPubMedGoogle Scholar
  33. Papayannopoulou T, Nakamoto B (1993) Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc Natl Acad Sci U S A 90(20):9374–9378CrossRefPubMedCentralPubMedGoogle Scholar
  34. Papayannopoulou T, Scadden DT (2008) Stem-cell ecology and stem cells in motion. Blood 111(8):3923–3930. doi:10.1182/blood-2007-08-078147CrossRefPubMedCentralPubMedGoogle Scholar
  35. Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS (1995) The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci U S A 92(21):9647–9651CrossRefPubMedCentralPubMedGoogle Scholar
  36. Papayannopoulou T, Priestley GV, Nakamoto B, Zafiropoulos V, Scott LM (2001) Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins. Blood 98(8):2403–2411. doi:10.1182/blood.V98.8.2403CrossRefPubMedGoogle Scholar
  37. Podar K, Zimmerhackl A, Fulciniti M, Tonon G, Hainz U, Tai YT, Vallet S, Halama N, Jager D, Olson DL, Sattler M, Chauhan D, Anderson KC (2011) The selective adhesion molecule inhibitor Natalizumab decreases multiple myeloma cell growth in the bone marrow microenvironment: therapeutic implications. Br J Haematol 155(4):438–448. doi:10.1111/j.1365-2141.2011.08864.xCrossRefPubMedGoogle Scholar
  38. Priestley GV, Scott LM, Ulyanova T, Papayannopoulou T (2006) Lack of alpha4 integrin expression in stem cells restricts competitive function and self-renewal activity. Blood 107(7):2959–2967. doi:10.1182/blood-2005-07-2670CrossRefPubMedCentralPubMedGoogle Scholar
  39. Redondo-Munoz J, Ugarte-Berzal E, Garcia-Marco JA, del Cerro MH, Van den Steen PE, Opdenakker G, Terol MJ, Garcia-Pardo A (2008) Alpha4beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells. Blood 112(1):169–178. doi:10.1182/blood-2007-08-109249CrossRefPubMedGoogle Scholar
  40. Rettig MP, Ansstas G, DiPersio JF (2012) Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4. Leukemia 26(1):34–53. doi:10.1038/leu.2011.197CrossRefPubMedCentralPubMedGoogle Scholar
  41. Rose DM, Cardarelli PM, Cobb RR, Ginsberg MH (2000) Soluble VCAM-1 binding to α4 integrins is cell-type specific and activation dependent and is disrupted during apoptosis in T cells. Blood 95(2):602–609PubMedGoogle Scholar
  42. Rossi D, Zucchetto A, Rossi FM, Capello D, Cerri M, Deambrogi C, Cresta S, Rasi S, De Paoli L, Bodoni CL, Bulian P, Del Poeta G, Ladetto M, Gattei V, Gaidano G (2008) CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia. Haematologica 93(10):1575–1579. doi:10.3324/haematol.13103CrossRefPubMedGoogle Scholar
  43. Rossi D, Bodoni CL, Zucchetto A, Rasi S, De Paoli L, Fangazio M, Rossi FM, Ladetto M, Gattei V, Gaidano G (2010) Low CD49d expression and long telomere identify a chronic lymphocytic leukemia subset with highly favourable outcome. Am J Hematol 85(8):619–622. doi:10.1002/ajh.21756CrossRefPubMedGoogle Scholar
  44. Shanafelt TD, Geyer SM, Bone ND, Tschumper RC, Witzig TE, Nowakowski GS, Zent CS, Call TG, Laplant B, Dewald GW, Jelinek DF, Kay NE (2008a) CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential. Br J Haematol 140(5):537–546. doi:10.1111/j.1365-2141.2007.06965.xCrossRefPubMedGoogle Scholar
  45. Shanafelt TD, Hanson C, Dewald GW, Witzig TE, LaPlant B, Abrahamzon J, Jelinek DF, Kay NE (2008b) Karyotype evolution on fluorescent in situ hybridization analysis is associated with short survival in patients with chronic lymphocytic leukemia and is related to CD49d expression. J Clin Oncol 26(14):e5–e6. doi:10.1200/JCO.2008.16.7874CrossRefPubMedCentralPubMedGoogle Scholar
  46. Shattil SJ, Kim C, Ginsberg MH (2010) The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 11(4):288-300. doi:10.1038/nrm2871CrossRefPubMedCentralPubMedGoogle Scholar
  47. Sil H, Sen T, Chatterjee A (2011) Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9. Oncol Res 19(7):335–348CrossRefPubMedGoogle Scholar
  48. Staunton DE, Lupher ML, Liddington R, Gallatin WM (2006) Targeting integrin structure and function in disease. Adv Immunol 91:111–157. doi:10.1016/S0065-2776(06)91003-7CrossRefPubMedGoogle Scholar
  49. 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):682–686PubMedGoogle Scholar
  50. Takagi J, Springer TA (2002) Integrin activation and structural rearrangement. Immunol Rev 186:141–163CrossRefPubMedGoogle Scholar
  51. 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.2009.27.5693CrossRefPubMedCentralPubMedGoogle Scholar
  52. Woodside DG, Vanderslice P (2008) Cell adhesion antagonists: therapeutic potential in asthma and chronic obstructive pulmonary disease. BioDrugs 22(2):85–100CrossRefPubMedGoogle Scholar
  53. Yonekawa K, Harlan JM (2005) Targeting leukocyte integrins in human diseases. J Leukoc Biol 77(2):129–140. doi:10.1189/jlb.0804460CrossRefPubMedGoogle Scholar
  54. Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, Levis M, Rubin JB, Negrin RR, Estey EH, Konoplev S, Andreeff M, Konopleva M (2009) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood 113(24):6215–6224. doi:10.1182/blood-2008-05-158311CrossRefPubMedCentralPubMedGoogle Scholar
  55. Zhang B, Ho Yin W, Huang Q, Maeda T, Lin A, Lee S-u, Hair A, Holyoake Tessa L, Huettner C, Bhatia R (2012) Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21(4):577–592CrossRefPubMedCentralPubMedGoogle Scholar
  56. Zucchetto A, Benedetti D, Tripodo C, Bomben R, Dal Bo M, Marconi D, Bossi F, Lorenzon D, Degan M, Rossi FM, Rossi D, Bulian P, Franco V, Del Poeta G, Deaglio S, Gaidano G, Tedesco F, Malavasi F, Gattei V (2009) CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. Cancer Res 69(9):4001–4009. doi:10.1158/0008-5472.CAN-08-4173CrossRefPubMedGoogle Scholar

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© Springer-Verlag New York 2015

Authors and Affiliations

  1. 1.Department of Medicine, Division of HematologyFred Hutchinson Cancer Research CenterSeattleUSA

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