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Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia

Nature Medicine volume 9, pages 1158–1165 (2003)Cite this article

A Corrigendum to this article was published on 01 May 2005

Abstract

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.

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Figure 1: Effect of extracellular matrix proteins on chemosensitivity of AML cell lines.
Figure 2: VLA-4-mediated adhesion to fibronectin protects AML cells from apoptosis induced by anticancer drugs.
Figure 3: Mechanisms by which VLA-4–fibronectin interaction mediates inhibition of apoptosis induced in an AML cell line by anticancer drugs.
Figure 4: Combination therapy using VLA-4-specific antibodies and AraC.
Figure 5: VLA-4-mediated adhesion to fibronectin protects patients' leukemic cells from apoptosis induced by anticancer drugs.
Figure 6: Prognosis of AML patients in relation to VLA-4 expression on leukemic cells, and effect of VLA-4-specific antibodies, combined with AraC, on MRD in mice inoculated with leukemic cells.

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Acknowledgements

The authors thank P. Olley and K. Litton for editorial assistance.

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Author notes

  1. Takuya Matsunaga and Naofumi Takemoto: These authors contributed equally to this work.

Authors and Affiliations

  1. Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-0061, Japan

    Takuya Matsunaga, Naofumi Takemoto, Tsutomu Sato, Rishu Takimoto, Ikuta Tanaka, Akihito Fujimi, Takehide Akiyama, Hiroyuki Kuroda, Yutaka Kawano, Masayoshi Kobune, Junji Kato & Yoshiro Niitsu

  2. Department of Internal Medicine, Higashi Sapporo Hospital, 3-3, Higashi Sapporo, Shiroishi-ku, Sapporo, 003-0003, Japan

    Yasuo Hirayama & Sumio Sakamaki

  3. Department of Internal Medicine, Japanese Red Cross Asahikawa Hospital, 1-1, Akebono-cho, Asahikawa, 070-0061, Japan

    Kyuhei Kohda

  4. Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo, 108-8639, Japan

    Kensuke Miyake

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Matsunaga, T., Takemoto, N., Sato, T. 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 9, 1158–1165 (2003). https://doi.org/10.1038/nm909

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