Article

Chronic myeloid leukemia: Mechanisms of blastic transformation

Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 41230, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2010; 120(7):2254-64. DOI: 10.1172/JCI41246
Source: PubMed

ABSTRACT

The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.

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    • "CML occurs at an incidence rate of 1-2 cases per 100,000 adults and accounts for approximately 15% of newly diagnosed cases of leukemia in adults, with an estimated 5920 new cases and 610 deaths in the US in 2013 (Jabbour and Kantarjian, 2012; Soverini et al., 2014). In the West, the median age of onset is 50-60 years, which reflects the average age of the population (Perrotti et al., 2010). Central to the pathogenesis of CML is the fusion of the ABL gene on chromosome 9 with the BCR gene on chromosome 22, which results in expression of the oncoprotein, BCR-ABL (Jabbour and Kantarjian, 2012). "
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    ABSTRACT: Our study aimed to investigate the association between multidrug resistance (MDR1) gene polymorphisms and the response to imatinib (IM) in chronic myeloid leukemia (CML). An electronic databases in PubMed, Cochrane Library, Wanfang, China National Knowledge Infrastructure, and VIP were searched using combinations of keywords relating to MDR1 polymorphisms and the response to IM in CML. Studies retrieved from database searches were screened using stringent inclusion and exclusion criteria. The Comprehensive Meta-analysis 2.0 software was utilized for all statistical analyses. In total, 186 studies were initially retrieved, and 10 studies, involving 987 CML patients, were eventually included in this meta-analysis. Results of our study revealed no significant associations between MDR1 rs1045642, rs1128503, and rs2032582 polymorphisms and major molecular response and complete molecular response in CML patients. Significant differences were observed in the genotype frequencies of MDR1 rs1128503 under homozygous, heterozygous, and recessive models, between CML patients sensitive and resistant to IM. A significant difference in genotype frequencies of MDR1 rs2032582 was also observed under allele, homozygous, heterozygous, and recessive models between CML patients sensitive and resistant to IM. In conclusion, based on our meta-analysis, the MDR1 polymorphisms, rs1045642, rs1128503, and rs2032582, are not directly correlated with the curative effect of IM treatment of CML patients.
    Preview · Article · Nov 2015 · Genetics and molecular research: GMR
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    • "CML-CP is characterized by an increase in immature and mature myeloid cells with maintenance of hematopoietic differentiation, whereas CML-AP and BC are characterized by more number of immature cells with great reduction in hematopoietic differentiation process and are associated with increased resistance to apoptosis (Calabretta and Perrotti, 2004). More than 90% of CML patients are diagnosed when their disease is in a relatively early phase known as the chronic phase (CP) (Perrotti et al, 2010). CML-BC is characterized by enhanced genomic instability, dysregulated proliferation and arrested differentiation of hematopoietic progenitors. "
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    ABSTRACT: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm of the hematopoietic system, characterized by the presence of the BCR-ABL oncoprotein due to the chromosomal translocation t (9;22). This oncoprotein has elevated tyrosine kinase activity, which leads to enhanced proliferation, reduced differentiation and apoptosis, increased angiogenesis etc. Even though several targeted tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib etc. are being employed in treating CML, a proportion of patients (25-30%) exhibit resistance to TKIs leading to treatment failure and unchecked disease progression. Progression of CML may be due to genetic instability which include chromosomal translocations, mutations, polymorphisms and gene amplification which ultimately causes up and down regulation of genes in various pathways including angiogenesis. Increased angiogenesis is associated with CML due to the up regulation of various angiogenic factors and their transcriptional regulators, which in turn has been found to lead to disease progression to advanced phases, as the protein products of these genes may act synergistically with BCR-ABL oncoprotein in advancing the disease. Single nucleotide polymorphisms (SNPs) are one of the causes for up regulation of antigenic genes and are associated with susceptibility and progression of CML by affecting therapeutic outcome. This review focuses mainly on the role of upregulated pro-angiogenic factors-VEGF, IL-8 and their transcriptional regulators HIF1α, NF-kB and also the role of SNPs in these genes in disease susceptibility, progression, drug response, prognosis and survival in CML patients. Identification of SNPs and up regulated genes of angiogenesis may serve as biomarkers for predicting disease progression, drug response, prognosis etc. Anti-angiogenic therapy is aimed at targeting the new blood vessels that supply nutrients to rapidly growing tumor cells. Combinations of targeted therapy and anti-angiogenic therapy may serve as the novel therapeutic strategies in overcoming drug resistance and thereby preventing the disease progression in CML.
    Full-text · Article · Jul 2014
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    • "Some patients progressed directly to CML-BP without an intermediate phase of acceleration. CML-BP is associated with dramatic changes in the leukemia cell phenotype: enhanced ''stemness'', uncontrolled proliferation and invasion, abrogated differentiation, and early resistance to TKIs [7] [8]. Previous researches demonstrated that response to imatinib in patients with advanced CML was less prominent than that in CML-CP [9] [10]. "
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    ABSTRACT: Ribosomal protein S27a (RPS27a) could perform extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. The high expression level of RPS27a was reported in solid tumors, and we found that the expression level of RPS27a was up-regulated in advanced-phase chronic myeloid leukemia (CML) and acute leukemia (AL) patients. In this study, we explored the function of RPS27a in leukemia cells by using CML cell line K562 cells and its imatinib resistant cell line K562/G01 cells. It was observed that the expression level of RPS27a was high in K562 cells and even higher in K562/G01 cells. Further analysis revealed that RPS27a knockdown by shRNA in both K562 and K562G01 cells inhibited the cell viability, induced cell cycle arrest at S and G2/M phases and increased cell apoptosis induced by imatinib. Combination of shRNA with imatinib treatment could lead to more cleaved PARP and cleaved caspase-3 expression in RPS27a knockdown cells. Further, it was found that phospho-ERK(p-ERK) and BCL-2 were down-regulated and P21 up-regulated in RPS27a knockdown cells. In conclusion, RPS27a promotes proliferation, regulates cell cycle progression and inhibits apoptosis of leukemia cells. It appears that drugs targeting RPS27a combining with tyrosine kinase inhibitor (TKI) might represent a novel therapy strategy in TKI resistant CML patients.
    Preview · Article · Apr 2014 · Biochemical and Biophysical Research Communications
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