Regulation of c-Myc ubiquitination controls chronic myelogenous leukemia initiation and progression Academic Article uri icon

Overview

MeSH Major

  • F-Box Proteins
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases

abstract

  • The molecular mechanisms regulating leukemia-initiating cell (LIC) function are of important clinical significance. We use chronic myelogenous leukemia (CML) as a model of LIC-dependent malignancy and identify the interaction between the ubiquitin ligase Fbw7 and its substrate c-Myc as a regulator of LIC homeostasis. Deletion of Fbw7 leads to c-Myc overexpression, p53-dependent LIC-specific apoptosis, and the eventual inhibition of tumor progression. A decrease of either c-Myc protein levels or attenuation of the p53 response rescues LIC activity and disease progression. Further experiments showed that Fbw7 expression is required for survival and maintenance of human CML LIC. These studies identify a ubiquitin ligase:substrate pair regulating LIC activity, suggesting that targeting of the Fbw7:c-Myc axis is an attractive therapy target in refractory CML.

publication date

  • March 18, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3609428

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2013.01.025

PubMed ID

  • 23518350

Additional Document Info

start page

  • 362

end page

  • 75

volume

  • 23

number

  • 3