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


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-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.
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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.
    Biochemical and Biophysical Research Communications 04/2014; 446(4). DOI:10.1016/j.bbrc.2014.03.086 · 2.30 Impact Factor
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    • "Mechanisms of CML progression in progenitors have been well established [8, 77] and are not in the focus of this review. A myriad of secondary, cooperating genetic mutations [8, 77] and gene expression changes [78] have been shown to be associated with the reprogramming of progenitors into secondary leukemia initiating cells. Some of these mutations obviously directly or indirectly disrupt the Arf-p53 tumor surveillance pathway highlighting its importance during progression. "
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    ABSTRACT: Deregulated BCR-ABL oncogenic activity leads to transformation, oncogene addiction and drives disease progression in chronic myeloid leukemia (CML). Inhibition of BCR-ABL using Abl-specific kinase inhibitors (TKI) such as imatinib induces remarkable clinical responses. However, approximately only less than 15 % of all chronic-phase CML patients will remain relapse-free after discontinuation of imatinib in deep molecular remission. It is not well understood why persisting CML cells survive under TKI therapy without developing clonal evolution and frank TKI resistance. BCR-ABL expression level may be critically involved. Whereas higher BCR-ABL expression has been described as a pre-requisite for malignant CML stem cell transformation and CML progression to blast crisis, recent evidence suggests that during persistence TKI select for CML precursors with low BCR-ABL expression. Genetic, translational and clinical evidence is discussed to suggest that TKI-induced maintenance of low BCR-ABL signaling output may be potently tumor suppressive, because it abrogates oncogenic addiction.
    Current Hematologic Malignancy Reports 02/2014; 9(1). DOI:10.1007/s11899-013-0196-8 · 2.20 Impact Factor
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