Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells
Cristian Bellodi, … , Paolo Salomoni, Bruno Calabretta
Cristian Bellodi, … , Paolo Salomoni, Bruno Calabretta
Published April 13, 2009
Citation Information: J Clin Invest. 2009;119(5):1109-1123. https://doi.org/10.1172/JCI35660.
View: Text | PDF | Corrigendum
Research Article Hematology Article has an altmetric score of 16

Targeting autophagy potentiates tyrosine kinase inhibitor–induced cell death in Philadelphia chromosome–positive cells, including primary CML stem cells

  • Text
  • PDF
Abstract

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.

Authors

Cristian Bellodi, Maria Rosa Lidonnici, Ashley Hamilton, G. Vignir Helgason, Angela Rachele Soliera, Mattia Ronchetti, Sara Galavotti, Kenneth W. Young, Tommaso Selmi, Rinat Yacobi, Richard A. Van Etten, Nick Donato, Ann Hunter, David Dinsdale, Elena Tirrò, Paolo Vigneri, Pierluigi Nicotera, Martin J. Dyer, Tessa Holyoake, Paolo Salomoni, Bruno Calabretta

×

Figure 7

Autophagy is induced in IM-treated primary CML cells and acts as a survival mechanism.

Options: View larger image (or click on image) Download as PowerPoint
Autophagy is induced in IM-treated primary CML cells and acts as a survi...
(A) Accumulation of LC3-II in IM-treated CD34+ CML (M351T) cells. Cells were treated with IM (2 μM) or left untreated. Extracts were probed with anti-LC3 and anti-GRB2 antibodies. LC3-II/LC3-I ratio was determined by densitometric analysis. (B) CQ potentiates the effect of IM in clonogenic assays. CD34+ CML cells were plated in methylcellulose in the presence or in the absence of IM (0.5 or 1.0 μM) and CQ (10.0 μM). Colonies were counted 10 days later. Values (expressed as percentage of control) are representative of 3 independent experiments. (C) siRNA-mediated downregulation of ATG5 or ATG7 expression enhances IM-induced inhibition of colony formation. CD34+ CML cells were transfected with control or ATG5 or ATG7 siRNAs and, 24 hours later, left untreated or treated with IM (1 μM). Twenty-four hours later, cells were plated in methylcellulose in the presence or absence of IM. Colonies were counted 10 days later. Values are representative of 2 independent experiments. Values represent mean ± SEM (B and C). (D) ATG5 and ATG7 levels in siRNA transfected CML cells. Western blots show ATG5 and ATG7 expression in M351T CML-CP lysates 24 hours after transfection with scrambled or Atg5- or Atg7-specific siRNA. GRB2 levels were measured as loading control. The asterisk indicates that bands are not specific for LC3.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Posted by 1 X users
Referenced in 4 patents
Mentioned by 1 peer review sites
Highlighted by 1 platforms
228 readers on Mendeley
See more details