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 Druker

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)396-409
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number1
DOIs
StatePublished - Jan 4 2011

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Myeloid Progenitor Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia
Therapeutics
Survival
Oncogene Proteins
Myeloid Cells
Oncogenes
Imatinib Mesylate
Cytokines
Recurrence
Growth

ASJC Scopus subject areas

  • Medicine(all)

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

In: Journal of Clinical Investigation, Vol. 121, No. 1, 04.01.2011, p. 396-409.

Research output: Contribution to journalArticle

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