title: Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia.
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.
authors.affiliation: Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-0061, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takemoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Sato
authors.forename: Rishu
authors.initials: R
authors.lastname: Takimoto
authors.forename: Ikuta
authors.initials: I
authors.lastname: Tanaka
authors.forename: Akihito
authors.initials: A
authors.lastname: Fujimi
authors.forename: Takehide
authors.initials: T
authors.lastname: Akiyama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuroda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kobune
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hirayama
authors.forename: Sumio
authors.initials: S
authors.lastname: Sakamaki
authors.forename: Kyuhei
authors.initials: K
authors.lastname: Kohda
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D016513:Mice, SCID; D018365:Neoplasm, Residual; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D015996:Survival Rate; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; D005353:Fibronectins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C494918:AKT1 protein, human