Interaction Between Leukemic-Cell VLA-4 and Stromal Fibronectin Is a Decisive Factor for Minimal Residual Disease of Acute Myelogenous Leukemia

Nat Med. 2003 Sep;9(9):1158-65. doi: 10.1038/nm909. Epub 2003 Aug 3.

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.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use
  • Cytarabine / therapeutic use
  • Drug Resistance, Neoplasm
  • Fibronectins / metabolism*
  • Humans
  • Integrin alpha4beta1 / drug effects
  • Integrin alpha4beta1 / immunology
  • Integrin alpha4beta1 / metabolism*
  • Integrin alpha5beta1 / metabolism
  • Leukemia / drug therapy
  • Leukemia / metabolism
  • Leukemia / pathology
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / mortality
  • Mice
  • Mice, SCID
  • Neoplasm, Residual
  • Phosphatidylinositol 3-Kinases / metabolism
  • Predictive Value of Tests
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Stromal Cells / metabolism
  • Survival Rate
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Antibodies
  • Antimetabolites, Antineoplastic
  • Fibronectins
  • Integrin alpha4beta1
  • Integrin alpha5beta1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Cytarabine
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt