共查询到20条相似文献,搜索用时 15 毫秒
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Rapid in vivo assay for murine lymphatic leukaemia viruses 总被引:4,自引:0,他引:4
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Thymus and bone marrow derived lymphatic leukaemia in mice 总被引:7,自引:0,他引:7
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The clinical success of the ABL tyrosine kinase inhibitor imatinib in chronic myeloid leukaemia (CML) serves as a model for molecularly targeted therapy of cancer, but at least two critical questions remain. Can imatinib eradicate leukaemic stem cells? What are the dynamics of relapse due to imatinib resistance, which is caused by mutations in the ABL kinase domain? The precise understanding of how imatinib exerts its therapeutic effect in CML and the ability to measure disease burden by quantitative polymerase chain reaction provide an opportunity to develop a mathematical approach. We find that a four-compartment model, based on the known biology of haematopoietic differentiation, can explain the kinetics of the molecular response to imatinib in a 169-patient data set. Successful therapy leads to a biphasic exponential decline of leukaemic cells. The first slope of 0.05 per day represents the turnover rate of differentiated leukaemic cells, while the second slope of 0.008 per day represents the turnover rate of leukaemic progenitors. The model suggests that imatinib is a potent inhibitor of the production of differentiated leukaemic cells, but does not deplete leukaemic stem cells. We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer. 相似文献
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Puente XS Pinyol M Quesada V Conde L Ordóñez GR Villamor N Escaramis G Jares P Beà S González-Díaz M Bassaganyas L Baumann T Juan M López-Guerra M Colomer D Tubío JM López C Navarro A Tornador C Aymerich M Rozman M Hernández JM Puente DA Freije JM Velasco G Gutiérrez-Fernández A Costa D Carrió A Guijarro S Enjuanes A Hernández L Yagüe J Nicolás P Romeo-Casabona CM Himmelbauer H Castillo E Dohm JC de Sanjosé S Piris MA de Alava E San Miguel J Royo R Gelpí JL Torrents D Orozco M Pisano DG 《Nature》2011,475(7354):101-105
Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. 相似文献
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L Zech G Gahrton L Hammarstr?m G Juliusson H Mellstedt K H Robèrt C I Smith 《Nature》1984,308(5962):858-860
Rare cases of chronic lymphocytic leukaemia (CLL) in man stem from the malignant proliferation of T cells. The disease is usually more aggressive clinically than B-cell-derived CLL. Various haematological tumours are associated with specific chromosome aberrations (for example, refs 1, 2). Only limited numbers of T-cell CLL patients have so far been studied cytogenetically and, whereas chromosome 12 seems particularly to be involved in B-cell CLL, several markers have been found in T-cell tumours. Recently, by stimulating malignant clones with different mitogens, novel chromosome abnormalities have been detected in T-cell CLL. Using the same approach for additional cases of T-cell CLL, we now report that the most consistent chromosome change is an inversion of the long arm of chromosome 14, inv(14)(q11 q32), in four of five patients. Another remarkable chromosome aberration is trisomy for the long arm of chromosome 8, found in three of five patients. 相似文献
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Fused transcript of abl and bcr genes in chronic myelogenous leukaemia 总被引:29,自引:0,他引:29
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Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia 总被引:3,自引:0,他引:3
C M Morris A E Reeve P H Fitzgerald P E Hollings M E Beard D C Heaton 《Nature》1986,320(6059):281-283
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Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia 总被引:67,自引:0,他引:67
N Heisterkamp J R Stephenson J Groffen P F Hansen A de Klein C R Bartram G Grosveld 《Nature》1983,306(5940):239-242
The human c-ab1 oncogene maps within the region (q34-qter) of chromosome 9 which is translocated to chromosome 22, the Philadelphia (Ph') chromosome, in chronic myelocytic leukaemia (CML). The position of the Ph' chromosomal break point is shown to be variable and, in one CML patient, has been localized immediately 5' of, or within, the c-ab1 oncogene. A DNA restriction fragment corresponding to this site has been molecularly cloned and shown to represent a chimaeric fragment of DNA from chromosomes 9 and 22. 相似文献
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Cytological identification of radiation-chimaeras 总被引:26,自引:0,他引:26
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Altered adhesive interactions with marrow stroma of haematopoietic progenitor cells in chronic myeloid leukaemia 总被引:12,自引:0,他引:12
Normal haematopoietic cell regulation involves interaction between marrow stromal cells and haematopoietic progenitor cells which may be facilitated by specific recognition and adhesion. Some leukaemogenic events might produce a selective growth advantage by altering this regulatory network, possibly by diminishing the capacities of cells to adhere to stromal elements. Using an in vitro culture system which allows investigation of adhesion to stromal layers and subsequent colony formation by blast colony-forming cells (B1-CFC) in normal marrow and Ph+ chronic myeloid leukaemic (CML) blood, we compared the adhesive properties of normal and malignant progenitor cells. We present evidence that altered adhesive interactions between primitive progenitor cells and marrow stromal cells occur in CML. 相似文献
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