Chronic Myeloid Leukemia: How to Overcome the Tyrosine Kinase Inhibitors Resistance
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 18, Issue 2
Abstract
Chronic Myeloid Leukemia (CML) is a cancer stem cell-based hematopoietic malignancy that is characterized by unregulated myeloid cell proliferation in the bone marrow and peripheral blood. Tyrosine kinase inhibitors (TKIs) has been the front-line therapy for CML by effectively inhibiting the BCR-ABL oncoprotein and achieved durable clinical responses in many patients. However, resistance to TKI frequently occurs and poses a major obstacle for the treatment of CML. Recent studies have drawn a more complete picture of TKI resistance that it involves multiple aspects of CML cells, including deregulated signaling, BCR-ABL mutations, as well as the intrinsic insensitivity of CML stem cells. Here, we review the history of CML, current therapy challenges and solutions. The first description of Chronic Myeloid Leukemia (CML) dates back to 1840s, when David Craigie and his colleges described a few cases of patients with fever, splenomegaly and leukocytosis, and subsequent death [1]. In the 1960s, Nowell and Hungerford, and later by others, noticed a consistent feature, the presence of a minute chromosome--Philadelphia chromosome (Ph chromosome), from the blood of CML patients [2]. Ph chromosome was further characterized by Rowley to be originated from a reciprocal chromosomal translocation event, designated t (9;22) [3]. The major outcome of this chromosomal translocation is the production of an oncogenic fusion protein, BCR-ABL, and the causal relationship of BCR-ABL and CML was further established by Daley et al by showing induction of CML-like leukemia in mice by virally transducing BCR-ABL gene into murine stem cells [4]. CML is a myeloproliferative disease (MPD), characterized by elevated levels of white blood cell count, with the majority of cells being mature neutrophils, myelocytes, basophils and eosinophils, usually with few blasts [5]. The uncontrolled leukemia cell accumulation in the peripheral blood and bone marrow, and patients finally succumb to disease with subsequent infiltration of leukemic cells into lung and liver [4]. CML has a median onset age at 53 with the annual incidence of about one to two cases per 100,000 people [6]. CML patients are usually identified in chronic, accelerated and blast crisis phases [5]. Chronic phase patients usually have 4-5 years of latency, and majority of the cells in peripheral blood are neutrophils. BCR-ABL signaling promotes genomic instability and accumulation of additional mutations in CML cells, leading to arrest of CML cells at immature blast cell stage and disease progression. Some CML patients may go through an accelerated phase of about 6-9 months, while other patients may directly enter terminal blast crisis phase [7].
Authors and Affiliations
Yinzhe GE, Mang XIAO
Keywords
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- EP ID EP620469
- DOI 10.26717/BJSTR.2019.18.003118
- Views 184
- Downloads 0
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