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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 Article has an altmetric score of 7

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

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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.

Authors

Amie S. Corbin, Anupriya Agarwal, Marc Loriaux, Jorge Cortes, Michael W. Deininger, Brian J. Druker

×

Ph+ stem cell percentage in the CD34+CD38- fraction and sensitivity to Imatinib

Submitter: Manuela Marega | m.marega@campus.unimib.it

Authors: Luca Mologni, Rocco Piazza, and Carlo Gambacorti-Passerini

University of Milano-Bicocca

Published February 10, 2011

In their recent report (1), Corbin et al. describe the effects of imatinib treatment on CD34+CD38- (defined as HSCs) from newly diagnosed chronic phase patients and demonstrated the survival of these cells to be independent of Bcr/Abl kinase activity. We feel that an important piece of information is missing, i.e. the percent Bcr/Abl+ cells within the HSC compartment. The authors detected no change in Ph-positivity in the unsorted Lin- pool after treatment with imatinib, compared to untreated cells, counting about 100% Ph+ cells by FISH. However, they did not verify the percentage of Bcr/Abl in the CD34+CD38- cell fraction. It is important to verify the percentage of Ph+ cells, not only the activity, since the lack of biological activity observed after Bcr/Abl inhibition could be due to a low percent of these cells inside the HSC population. At the last ASH meeting, Mustjoki et all. showed high variability of percent Ph+ cells in the CD34+CD38- population: the proportion of Ph+ cells was significantly lower in the more primitive CD34+CD38- fraction compared to CD34+CD38+ fraction and unfractionated BM (79%, 96% and 96%, respectively). The range of Ph+ stem cells at the time of diagnosis varied from 1 to 100%. The knowledge of how many of the CD34+CD38- cells are Ph+ (i.e. true imatinib targets) would permit better interpretation of the biological data. Another recent Letter to the Editor (2) showed that the proportion of Ph+ cells decreased in the CD34+CD38- cell fraction of CP patients after treatment with TKIs, in contrast to in vitro data showing resistance of CD34+CD38- cells to TKI therapy. In addition, IL1RAP could represent a marker for Ph+ CD34+CD38-: the expression of this receptor correlates with the positivity for Philadelphia chromosome in HSCs and could be useful to evaluate the number of Ph+ CD34+CD38- (3).

References

  1. Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Invest. 2011 Jan 4;121(1):396-409. doi:10.1172/JCI35721. Epub 2010 Dec 13.
  2. Mustjoki S, Rohon P, Rapakko K, Jalkanen S, Koskenvesa P, Lundán T, Porkka K. Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph(+)CD34(+)CD38(neg)) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy. Leukemia. 2010 Jan;24(1):219-22. Epub 2009 Sep 24.
  3. Järås M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, Lassen C,Olofsson T, Bjerrum OW, Richter J, Fioretos T. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16280-5. Epub2010 Aug 30.

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