Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Current targeted therapies designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein have made a significant breakthrough in the treatment of CML patients. However, CML remains a chronic disease that a patient must manage for life. Although tyrosine kinase inhibitors (TKI) therapy has completely transformed the prognosis of CML, it has made the therapeutic management more complex. The interruption of TKI treatment results in early disease progression because it does not eliminate quiescent CML stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML to achieve a permanent cure, and to allow TKI interruption. This review summarizes recent research done on alternative targeted therapies with a particular focus on some important signaling pathways (such as Alox5, Hedgehog, Wnt/b-catenin, autophagy, and PML) that have the potential to target CML stem cells and potentially provide cure for CML. 1. Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. The immediate cause of CML was discovered in 1960 by Nowell and Hungerford who described the presence of a small chromosome in the tumor cells of patients with CML, named Philadelphia (Ph) chromosome after the hometown of its discovery [1]. In 1973, Rowley showed that this abnormal Philadelphia chromosome was a result of a reciprocal translocation between chromosome 9 and chromosome 22 [2]. Later, it was shown that a large part of the abelson (abl) gene on chromosome 9 is translocated to the breakpoint cluster region (bcr) gene on chromosome 22 creating bcr-abl, a hybrid oncogene coding for the BCR-ABL fusion protein. BCR-ABL is a constitutively active tyrosine kinase leading to the dysregulation of downstream signaling pathways and the increased proliferation and survival of leukemic cells. The discovery of BCR-ABL was a key milestone in understanding CML and devising novel targeted therapies to treat it (reviewed in [3, 4]). CML is a relatively rare hematopoietic stem cell disorder with an annual incidence of 1-2 cases per 100,000 individuals [5]. Most CML patients are diagnosed with a chronic phase characterized by an uncontrolled proliferation of myeloid elements that retain their ability to differentiate, resulting in an abnormal number of mature granulocytes. Without effective therapy, chronic phase progresses through an accelerated phase into a rapidly fatal acute leukemia known as the blast
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