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 ...
    • 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)
    • Vascular Malformations (Apr 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
Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity
Amie S. Corbin, … , Michael W. Deininger, Brian J. Druker
Amie S. Corbin, … , Michael W. Deininger, Brian J. Druker
Published December 13, 2010
Citation Information: J Clin Invest. 2011;121(1):396-409. https://doi.org/10.1172/JCI35721.
View: Text | PDF | Erratum
Research Article Article has an altmetric score of 7

Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity

  • Text
  • PDF
Abstract

Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint — whether disease persistence is BCR-ABL dependent or independent — has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38–, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.

Authors

Amie S. Corbin, Anupriya Agarwal, Marc Loriaux, Jorge Cortes, Michael W. Deininger, Brian J. Druker

×

Figure 4

Proliferation and survival of CML progenitor cells in short-term imatinib culture.

Options: View larger image (or click on image) Download as PowerPoint
Proliferation and survival of CML progenitor cells in short-term imatini...
(A) Cell numbers of newly diagnosed CML or normal Lin– cells with or without imatinib were monitored daily during a 4-day culture in the absence of cytokines or in the presence of a cytokine cocktail that included SCF, FLT3 ligand, GCSF, IL-3, and IL-6. Normalized cell counts (mean ± SEM) are plotted for CML (n = 10) and normal (n = 6) cells treated or not with 5 μM imatinib. (B) Apoptosis in untreated versus imatinib cultures was evaluated by annexin-V staining (n = 3, CML and normal). Mean ± SEM on day 4 is shown for cultures with no cytokines and the 5-cytokine cocktail. Moreover, imatinib-treated CML cells costained with annexin-V, Lin cocktail, CD34, and CD38 on day 4 (n = 3) showed differing apoptosis frequencies in different cell types. (C) Percent BCR-ABL+ cells were determined by FISH following culture with or without 5 μM imatinib. (D) Fold expansion of Lin– cells (n = 3, CML and normal) with or without imatinib was evaluated following a 4-day culture in a cytokine cocktail that was serially diluted relative to the conditions in A. Error bars represent SEM.

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

Sign up for email alerts

Referenced in 24 patents
Highlighted by 1 platforms
334 readers on Mendeley
See more details