β-Arrestin1 promotes the self-renewal of the leukemia-initiating cell-enriched subpopulation in B-lineage acute lymphoblastic leukemia related to DNMT1 activity

Cancer Lett. 2015 Feb 1;357(1):170-178. doi: 10.1016/j.canlet.2014.11.025. Epub 2014 Nov 15.

Abstract

The self-renewal ability of the leukemia initiating cell-enriched subpopulation is critical for leukemia initiation and maintenance. However, the regulation of leukemia initiating cells for the leukemia progression is poorly understood. In this study, we observed that β-Arrestin1, a multiple-function protein, is elevated in leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients. The loss of β-Arrestin1 in leukemia initiating cells-enriched fraction attenuates its self-renewal capacity both in vitro and in vivo. Further experiments showed that the mRNA expression level of β-Arrestin1 is negatively correlated with that of PTEN in leukemia initiating cells-enriched fraction. Moreover, DNA methylation of the PTEN promoter region, the activity and expression of DNMTs were enhanced in the leukemia initiating cells-enriched fraction. The inhibition of DNMT1 activity impaired the self-renewal and increased expression of PTEN of leukemia initiating cells-enriched fraction. In addition, depletion of β-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction. Our study reveals a novel function of β-Arrestin1 in the regulation of the self-renewal of leukemia initiating cells-enriched fraction from B-lineage acute lymphoblastic leukemia patients related to DNMT1 activity, indicating that β-Arrestin1 is a potential therapeutic target in B-lineage acute lymphoblastic leukemia.

Keywords: B-lineage acute lymphocytic leukemia; DNA methyltransferases; Leukemia initiating cells-enriched fraction; Self-renewal; β-Arrestin1.

MeSH terms

  • Adolescent
  • Animals
  • Apoptosis / physiology
  • Arrestins / metabolism*
  • Child
  • DNA Methylation
  • Female
  • Heterografts
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • PTEN Phosphohydrolase / biosynthesis
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • beta-Arrestins

Substances

  • Arrestins
  • DMAP1 protein, human
  • Repressor Proteins
  • beta-Arrestins
  • PTEN Phosphohydrolase
  • PTEN protein, human