Posted by rob on April 29, 2010 under Uncategorized | 
Persistent splenomegaly during imatinib therapy and the definition of complete hematological response in chronic myelogenous leukemia.
Am J Hematol. 2010 May;85(5):386-9
Authors: Racil Z, Klamova H, Voglova J, Faber E, Razga F, Zackova D, Buresova L, Cetkovsky P, Mayer J
PMID: 20425803 [PubMed - in process]
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Clinical implications of c-Kit mutations in acute myelogenous leukemia.
Curr Hematol Malig Rep. 2009 Apr;4(2):77-82
Authors: Malaise M, Steinbach D, Corbacioglu S
c-Kit is a receptor tyrosine kinase (RTK) with a pivotal role in melanogenesis, gametogenesis, and hematopoiesis. Aberrantly activated RTK and related downstream signaling partners were identified as key elements in the molecular pathogenesis of several malignancies. This finding culminated in a two-class model integrating constitutive activating and maturation arrest-inducing mutations as key elements for the pathogenesis of acute myelogenous leukemia (AML). c-Kit is expressed by myeloblasts in about 60% to 80% of patients, and the most frequently observed activating RTK mutations in AML (next to FLT3) are mutations or internal tandem duplications in c-Kit, with an overall incidence of 17%. The identification of small-molecule tyrosine kinase inhibitors capable of blocking key kinase switches introduced a paradigm change in the treatment of diseases like gastrointestinal stromal tumors and chronic myelogenous leukemia. Despite encouraging preclinical data, it appears that a complex clonal disease like AML will probably benefit from a synergistic approach of targeted drugs used (at least for now) in combination with conventional chemotherapy.
PMID: 20425418 [PubMed - as supplied by publisher]
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Chronic myelogenous leukemia stem cells: What’s new?
Curr Hematol Malig Rep. 2009 Apr;4(2):66-73
Authors: Copland M
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that arises in the hematopoietic stem cell compartment. CML is one of the best-understood malignancies, as it results from a single genetic mutation, the fusion oncogene BCR-ABL, which has been widely studied. Specific tyrosine kinase inhibitors have been developed to target BCR-ABL in CML, but these agents fail to eliminate the CML stem cell population and thus are unlikely to cure CML. This article reviews recent developments in the biology and treatment of CML, specifically focusing on CML stem cells. Significant progress continues to be made in our understanding of CML stem cell biology, which has wider implications within the cancer stem cell field. We are also beginning to see the identification of novel therapies that specifically target the CML stem cell. These are exciting times in the quest to cure CML.
PMID: 20425417 [PubMed - in process]
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The role of molecular tests in acute myelogenous leukemia treatment decisions.
Curr Hematol Malig Rep. 2010 Apr;5(2):109-17
Authors: Motyckova G, Stone RM
The prognosis for patients with acute myelogenous leukemia (AML) is dependent on age, karyotype, and the genetics of the neoplastic cell. The molecular markers with prognostic impact include mutations in FLT3, NPM1, MLL, WT1, c-KIT, and expression levels of BAALC, NM1, ERG, and CXCR4. Gene expression profiles and microRNA expression patterns in AML may prove highly useful in defining the prognosis of AML. Cytogenetic and, increasingly, molecular findings are used in determining the best therapy for AML patients, especially the choice of whether to perform allogeneic stem cell transplantation.
PMID: 20425404 [PubMed - in process]
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Molecular Monitoring of BCR-ABL Transcripts in Patients With Chronic Myelogenous Leukemia: Is High Sensitivity of Clinical Value?
Curr Hematol Malig Rep. 2010 Apr;5(2):88-94
Authors: Norkin M, Schiffer CA
Monitoring of disease response during treatment with tyrosine kinase inhibitors of patients with chronic myelogenous leukemia dramatically changed after the introduction of real-time PCR, which allows quantification of BCR-ABL transcript levels with high sensitivity and precision. However, its role in patients who have achieved complete cytogenetic response is not entirely clear; incorrect interpretation of results could lead to unnecessary changes from an effective treatment. This review discusses the current evidence regarding the benefits, uncertainties, and potential drawbacks of molecular monitoring in patients with chronic myelogenous leukemia in chronic phase.
PMID: 20425401 [PubMed - in process]
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Analysis of copy number variations of BS69 in multiple types of hematological malignancies.
Ann Hematol. 2010 Apr 28;
Authors: Yang H, Zhang C, Zhao X, Wu Q, Fu X, Yu B, Shao Y, Guan M, Zhang W, Wan J, Huang X
BS69 was originally identified as an adenovirus E1A-binding protein and was found to be involved in multiple cellular events. A recent array-based study implicated the presence of copy number variations (CNVs) of BS69 in the genomes of acute myelogenous leukemia. CNVs are present in the general population at varying degrees and have been found to associate with various types of diseases including hematological malignancies. However, most of the current studies focused on the genome-wide screening of CNVs, and the functional impact of such regions needs to be extensively investigated in large amount of clinical samples. Thus, in our study, we collected 617 bone marrow samples from multi-types of hematological malignancies as well as healthy controls. We found significant association between the CNVs of BS69 and these hematological malignancies including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma (MM), and myelodysplastic syndrome (MDS). We also examined the expression of BS69 mRNA in the samples with one or two copies of DNA, and observed a weak yet positive correlation between the relative expression level and gene dosage. In general, the CNVs of BS69 have the potential to serve as a diagnostic indicator, alone or in combination with other markers, for hematological malignancies.
PMID: 20425112 [PubMed - as supplied by publisher]
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SKI-606 (Bosutinib) Blocks Prostate Cancer Invasion, Growth, and Metastasis In vitro and In vivo through Regulation of Genes Involved in Cancer Growth and Skeletal Metastasis.
Mol Cancer Ther. 2010 Apr 27;
Authors: Rabbani SA, Valentino ML, Arakelian A, Ali S, Boschelli F
In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 (Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro-computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression-associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 (bone morphogenetic protein 2), BMP-6 (bone morphogenetic protein 6), IL-8 (interleukin 8), and TGF-beta (transforming growth factor beta) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients. Mol Cancer Ther; 9(5); 1147-57. (c)2010 AACR.
PMID: 20423991 [PubMed - as supplied by publisher]
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A Bead-Based Activity Screen for Small-Molecule Inhibitors of Signal Transduction in Chronic Myelogenous Leukemia Cells.
Mol Cancer Ther. 2010 Apr 27;
Authors: Sylvester JE, Kron SJ
Chronic myelogenous leukemia is characterized by the presence of the chimeric BCR-ABL gene, which is expressed as the constitutively active Bcr-Abl kinase. Although kinase activity is directly responsible for the clinical phenotype, current diagnostic and prognostic methods focus on a genetic classification system in which molecularly distinct subcategories are used to predict patient responses to small-molecule inhibitors of the Bcr-Abl kinase. Point mutations in the kinase domain are a central factor regulating inhibitor resistance; however, compensatory signaling caused by the activation of unrelated kinases can influence inhibitor efficacy. Kinase activity profiling can be used as a complementary approach to genetic screening and allows direct screening of small-molecule inhibitors. We developed a quantitative assay to monitor tyrosine kinase activities and inhibitor sensitivities in a model of chronic myelogenous leukemia using peptide reporters covalently immobilized on Luminex beads. Kinase activity is quantified by nonlinear regression from well-specific internal standard curves. Using optimized synthetic substrates and peptides derived from native substrates as probes, we measured kinase inhibition in cell lysates by the signal transduction inhibitors imatinib and dasatinib. Taking advantage of a convenient 96-well plate format, this assay also allows a straightforward and quantitative analysis of the differential effects of ATP and inhibitors on kinase activity. This method for analyzing a focused signaling network benefits from rigorous statistical analysis and short processing times, thereby offering a powerful tool for drug discovery and clinical testing. Mol Cancer Ther; 9(5); 1469-81. (c)2010 AACR.
PMID: 20423990 [PubMed - as supplied by publisher]
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