Molecular pathways to CML stem cells

Imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), but it does not cure the disease. Many patients never achieve significant cytogenetic or molecular responses. Some develop resistance to the drug, while others are simply unable to tolerate it. Unfortunately, most will relapse if the drug is discontinued. This is particularly true in patients with advanced disease, who tend to develop resistance rapidly and are unlikely to achieve durable remission with single-agent tyrosine kinase inhibitor therapy. A growing body of evidence suggests that the reason imatinib does not cure CML is that it is unable to eradicate the leukemic stem cells (LSC). LSC are a tiny population of cancer cells with the capacity to recapitulate the disease. These quiescent cells have subverted properties of normal hematopoietic stem cells, allowing them to avoid apoptosis, evade innate immunity, renew themselves, and survive long term. Here, we review the studies that have identified the deregulated molecular pathways responsible for the generation of CML stem cells and discuss implications for therapy.