Suppression of autophagy by BCR/ABL

Abstract

Imatinib and second generation BCR/ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for patients with chronic myelogenous leukemia (CML); however, CML stem cells are intrinsically insensitive to the cell death-inducing effects of TKIs, allowing the persistence of a "reservoir" of BCR/ABL-expressing CML-initiating cells potentially responsible for disease relapse and progression. Although it is still controversial whether the "insensitivity" of CML stem cells to treatment with TKI is due to BCR/ABL-dependent or independent mechanisms, treatment with IM appears to suppress BCR/ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Recent evidence indicates that BCR/ABL suppresses and treatment of CML cells with IM/TKIs induces autophagy, a genetically-regulated process of adaptation to metabolic stress which could allow tumor cells to become metabolically inert enabling their survival under conditions that may mimic growth factor/nutrients deprivation. Based on this hypothesis, TKI-induced autophagy may "antagonize" TKI-induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring "sensitivity" of CML stem cells to treatment with IM/TKI. Consistent with this, phenotypically and functionally defined CML-enriched stem cells insensitive to treatment with TKI are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may improve the potent and specific effects of TKIs by rendering CML stem cells sensitive to these targeted therapies.

Figure 1.

Treatment with TKI may elicit different responses in distinct CML progenitor subsets. The response to TKI may be different in distinct CML progenitor subsets. One possibility is that in committed progenitors TKI preferentially activate cell death rather than autophagy. By contrast, more primitive progenitors (stem cells) would be more resistant to cell death due to their propensity to activate preferentially the process of autophagy. As a result, the debulking effect of TKIs would be accompanied by survival of resistant leukemic stem cells. Survival of these autophagy-prone stem cells would be responsible for promoting disease progression.

Figure 2.

Role of autophagy in the cancer stem cell pool. Induction of autophagy by TKI treatment may maintain CML stem cells by preventing cell death, inhibiting differentiation, or blocking cell cycle progression. Metabolism intermediates generated by autophagy may be also needed for maintenance of stem cells.