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 5

Inhibition of BCR-ABL activity in cultured CML Lin– cells.

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Inhibition of BCR-ABL activity in cultured CML Lin– cells. (A) Phosp...
(A) Phospho-CRKL and total phosphotyrosine levels in bulk cultured Lin– cells were analyzed by immunoblot. Untreated cells, 5 μM imatinib–treated cells in which imatinib was washed out then cultured without imatinib prior to immunoblots (washout), and cells treated continuously with 5 μM imatinib are shown from a representative sample (n = 3). Lanes were run on the same gel but were noncontiguous (white lines). (B) Phosphotyrosine levels were analyzed by intracellular FACS analysis in bulk cultured Lin– cells. Matched isotype was used to establish background staining in each population. Graphs represent mean ± SEM fluorescence signal relative to isotype control (n = 3).