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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Research Article

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 1

Inhibition of phosphotyrosine by imatinib in CML stem and progenitor cells.

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Inhibition of phosphotyrosine by imatinib in CML stem and progenitor cel...
(A) Intracellular phosphotyrosine levels were evaluated by FACS in Lin– CML cells costained for CD34, CD38, and CD133. Representative phosphotyrosine histograms are shown in CML committed progenitor (CD34+CD38+) and stem cell (CD34+CD38– and CD133+) populations treated for 4 hours with or without 5 μM imatinib (IM). FACS data are displayed on a logarithmic scale. Background signal was established in the same populations by staining with a matched isotype control. MFI ± SEM for phosphotyrosine signal of treated and untreated cells relative to isotype are shown (n = 10 [CML]; 3 [normal]). (B) Suppression of phosphotyrosine FACS signal by imatinib in primary CML stem and progenitor cell populations was compared with 3 BCR-ABL–expressing cell lines. Signal over isotype is shown as percent of untreated. A representative phosphotyrosine immunoblot is shown for the leukemic cell line Kcl22 treated or not with 5 μM imatinib. (C) Dose-dependent inhibition of BCR-ABL activity by imatinib in CD34+CD38+ and CD34+CD38– cells was evaluated by phosphotyrosine FACS in 3 independent CML samples. Signals are graphed as percent of untreated.