Molecular biological characteristics of the recruitment of hematopoietic stem cells from bone marrow niche in chronic myeloid leukemia

Int J Clin Exp Pathol. 2015 Oct 1;8(10):12595-607. eCollection 2015.

Abstract

Chronic myeloid leukemia (CML) can be contextualized as a disease of unregulated self-renewal of stem cells which exist in a quiescent state and are instructed to differentiate and mobilize to circulation under pathologic circumstances leading to tumor invasion and metastasis. Here we found that matrix metalloproteinase-9 (MMP-9), induced by TGF-β1, upregulated s-KitL and s-ICAM-1, permitting the transfer of c-kit(+) hematopoietic stem cells (HSCs) from the quiescent to proliferative niche in CML. Further study showed that this MMP-9 production was raised by CML specific BCR/ABL(+) oncogene mediated TGF-β1. Besides, phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was evidenced to govern this stem cell recruitment in CML pathogenesis. Overall, our observations defined a novel critical role for TGF-β1 induced PI3K/Akt/NF-κB signaling pathway in the recruitment of the malignant cells in CML by releasing s-KitL and s-ICAM-1 and this was through a distinct PI3K/Akt/NF-κB signaling pathway.

Keywords: Chronic myeloid leukemia (CML); TGF-β1; hematopoietic stem cell (HSC); matrix metalloproteinase-9 (MMP-9); mesenchymal stem cell (MSC); s-ICAM-1; s-KitL.

MeSH terms

  • Adolescent
  • Adult
  • Blotting, Western
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Movement / physiology*
  • Cells, Cultured
  • Coculture Techniques
  • Electrophoretic Mobility Shift Assay
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Immunoprecipitation
  • In Situ Hybridization, Fluorescence
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Middle Aged
  • NF-kappa B / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • Stem Cell Niche*
  • Transfection
  • Transforming Growth Factor beta1 / metabolism
  • Young Adult

Substances

  • NF-kappa B
  • RNA, Small Interfering
  • Transforming Growth Factor beta1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • MMP9 protein, human
  • Matrix Metalloproteinase 9