Aberrant Expression of Functional BAFF-system Receptors by Malignant B-cell Precursors Impacts Leukemia Cell Survival

PLoS One. 2011;6(6):e20787. doi: 10.1371/journal.pone.0020787. Epub 2011 Jun 8.

Abstract

Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies.We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-κB, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-δ, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms.This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • B-Cell Activating Factor / genetics
  • B-Cell Activation Factor Receptor / genetics*
  • B-Cell Maturation Antigen / genetics*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Leukemia / genetics
  • Leukemia / metabolism
  • Leukemia / pathology*
  • MAP Kinase Signaling System / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Sequence Data
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Precursor Cells, B-Lymphoid / metabolism*
  • Precursor Cells, B-Lymphoid / pathology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Transmembrane Activator and CAML Interactor Protein / genetics*
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / chemistry
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics

Substances

  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • B-Cell Maturation Antigen
  • NF-kappa B
  • TNFSF13B protein, human
  • Transmembrane Activator and CAML Interactor Protein
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases