Posted by rob on December 30, 2010 under Uncategorized | 
The genetics and clinical manifestations of telomere biology disorders.
Genet Med. 2010 Dec;12(12):753-64
Authors: Savage SA, Bertuch AA
Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10, and NHP2 encode components of telomerase or a telomerase-associated factor and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.
PMID: 21189492 [PubMed - in process]
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Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase and is effective treatment for patients with chronic myelogenous leukemia (CML) resistant to or intolerant of treatment with imatinib. Large granular lymphocytes (LGLs) normally account for only 10–15% of circulating mononuclear cells in adults with most LGLs having an NK-cell phenotype (CD3?, CD16+, CD56+). Proliferation of LGLs has been reported in a small number of patients treated with dasatinib. Mustjoki et al demonstrated that LGL proliferation occurred in both CML and Philadelphia chromosome positive ALL patients treated with dasatinib . Both T- and NK-cell phenotypes were observed in patients with LGL lymphocytosis. In patients with T-cell phenotypes, clonality was demonstrated through T-cell receptor gene rearrange…
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Imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, has dramatically changed the treatment of chronic myelogenous leukemia (CML). The estimated 6-year overall survival is 95% when only CML-related deaths were considered . However, imatinib is a very expensive agent (standard daily dose (400mg) costs 12,512 yen=140 US$ in Japan). Therefore, in developing countries, allogeneic hematopoietic stem cell transplantation is still performed as a first-line treatment for CML, since many patients are unable to afford the continuing treatment with imatinib. (Source: Leukemia Research)
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This report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine. (Source: Leukemia Research)
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In conclusion, our study points to p57Kip2 as a novel and precocious effector of BCR–ABL targeting drugs. (Source: Carcinogenesis)
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