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.

Suppression of Acquired Docetaxel Resistance in Prostate Cancer through Depletion of Notch- and Hedgehog-Dependent Tumor-Initiating Cells

“…Here, we provided evidence that a subpopulation of cells, which exhibits the Docetaxel-resistance phenotype in cell lines and prostate cancer tissues, satisfied the T-IC criteria. These results corroborate a growing body of evidence (Corbin et al, 2011; Ishikawa et al, 2007; Lonardo et al, 2011; Todaro et al, 2007; Yu et al, 2007) that T-ICs may contribute to disease progression by participating in chemotherapy resistance.…”

“…A number of studies have shown that tumor-initiating cells (T-ICs) may preferentially survive exposure to chemotherapy, providing an attractive rationale for relapse following initial tumor shrinkage with standard therapy (Corbin et al, 2011; Ishikawa et al, 2007; Lonardo et al, 2011; Todaro et al, 2007; Yu et al, 2007). Having demonstrated that CK − cells survive Docetaxel exposure in vitro and in vivo, we investigated the tumor-initiating capacity of these cells.…”

Label-retaining liver cancer cells are relatively resistant to sorafenib

“…This hypothesis continues to be controversial. Moreover, there is a paucity of data suggesting that CSC are indeed resistant to targeted therapy 6 7…”

Longitudinal Study to Assess the Clinical Significance of <b><i>MSI2</i></b> Expression in Chronic Myeloid Leukemia Patients

“…A prospective study would also assess whether it is the leukemic stem cells, known to be resistant to TKI therapy, with increased levels of MSI2 that are responsible for the progression to BC [4]. Such cells are expected to be relatively scarce at diagnosis, but would be selected for and proliferate at the expense of others during the course of TKI therapy.…”