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: 13.77). 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-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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    • "The clinical course in CML can be divided into a chronic phase (CP), an accelerated phase (AP), and a blast phase (BP), which is the terminal phase and resembles an acute leukemia [8] [9] [10]. Whereas in CP, BCR-ABL1 is a major driving force of cell survival and proliferation , additional factors and pro-oncogenic molecules, apart from BCR- ABL1, may play a more important or even decisive pathogenetic role in AP and BP [6] [7] [8] [9] [10]. A key feature in AP of CML is basophilia [11] [12]. "
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    ABSTRACT: Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
    Neoplasia (New York, N.Y.) 07/2012; 14(7):572-84. DOI:10.1593/neo.12724 · 5.40 Impact Factor
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    • "The time course for progression to BP is variable and the molecular mechanisms underlying disease progression are extremely complex. BCR- ABL-dependent pathways to blast transformation include an increase in genomic instability, telomere shortening, loss of tumor-suppressor function, and inhibition of tumor suppressors with cell regulatory functions [2] [3]. "
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    ABSTRACT: Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder characterized by the presence of the Philadelphia chromosome which resulted from the reciprocal translocation between chromosomes 9 and 22. The pathogenesis of CML involves the constitutive activation of the BCR-ABL tyrosine kinase, which governs malignant disease by activating multiple signal transduction pathways. The BCR-ABL kinase inhibitor, imatinib, is the front-line treatment for CML, but the emergence of imatinib resistance and other tyrosine kinase inhibitors (TKIs) has called attention for additional resistance mechanisms and has led to the search for alternative drug treatments. In this paper, we discuss our current understanding of mechanisms, related or unrelated to BCR-ABL, which have been shown to account for chemoresistance and treatment failure. We focus on the potential role of the influx and efflux transporters, the inhibitor of apoptosis proteins, and transcription factor-mediated signals as feasible molecular targets to overcome the development of TKIs resistance in CML.
    04/2012; 2012:671702. DOI:10.1155/2012/671702

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