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

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

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Figure 4

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

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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.