Chronic myeloid leukemia stem cells and developing therapies.

Chronic myeloid leukemia therapy has remarkably improved with the use of frontline BCR-ABL kinase inhibitors such that newly diagnosed patients have minimal disease manifestations or progression. Effective control of disease may also set the stage for eventual 'cure' of this leukemia. However, the existence of Philadelphia chromosome-positive leukemic cells that are unaffected by BCR-ABL inhibition represents a major barrier that may delay or prevent curative therapy with the current approaches. The most commonly reported mechanism of resistance to tyrosine kinase inhibitor-based therapies involves BCR-ABL gene mutations and amplification, but these changes may not be solely responsible for disease relapse when inhibitor-based therapies are curtailed. Therefore new targets may need to be defined before significant advancement in curative therapies is possible. Emerging evidence suggests that persistence of chronic myeloid leukemia stem cells or acquisition of stem cell-like characteristics prevents complete elimination of chronic myeloid leukemia by tyrosine kinase inhibition alone. This review focuses on several recently emerging concepts regarding the existence and characteristics of chronic myeloid leukemia stem cells. Definitions based on human primary cells and animal model studies are highlighted as are the potential signaling pathways associated with disease repopulating cells. Finally, several recently defined therapeutic targets and active compounds that have emerged from stem cell studies are described. Our goal is to provide an unbiased report on the current state of discovery within the chronic myeloid leukemia stem cell field and to orient the reader to emerging therapeutic targets and strategies that may lead to elimination of this leukemia.