Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity
Amie S. Corbin, Anupriya Agarwal, Marc Loriaux, Jorge Cortes, Michael W. Deininger, Brian J. Druker
Amie S. Corbin, Anupriya Agarwal, Marc Loriaux, Jorge Cortes, Michael W. Deininger, Brian J. Druker
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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 6

Survival and expansion of different CML stem and progenitor cell immunophenotypic and functional subtypes following culture with imatinib.

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Survival and expansion of different CML stem and progenitor cell immunop...
(A) Relative frequencies of Lin–, CD34+, CD34+CD38–, and quiescent cells prior to and following 4-day CML Lin– cell culture. Values are mean ± SEM percent of total population (n = 6 [CML]; 3 [normal]). (B) Absolute cell numbers (normalized relative to starting cell density) of Lin–, CD34+, and CD34+CD38–, and quiescent cells prior to and following culture with or without imatinib. Values are mean ± SEM (n = 6 [CML]; 2 [normal]). (C) Expansion of CD34+ and CD34+CD38– CML cell numbers in the presence of imatinib shown for individual patient samples. (D) Phosphotyrosine levels were analyzed by intracellular FACS analysis in CD34+CD38– and CD34+CD38+ cells following culture. Matched isotype was used to establish background staining in each population. Values are mean ± SEM fluorescence signal relative to isotype control (n = 3). (E) Colony-forming and LTC-IC assays of postculture CML progenitors (n = 3) were performed. CFCs were evaluated at 0, 3, and 6 weeks of culture on murine stromal cells. Mean ± SEM CFC numbers are shown as percent of untreated.