1,721,069 research outputs found
Oncogenic protein tyrosine kinases: Oncogenic derivatives of platelet-derived growth factor receptors
No full textPlatelet-derived growth factor receptors (PDGFRs) and their ligands, platelet-derived growth factors (PDGFs) play critical roles in mesenchymal cell migration and proliferation. In embryogenesis the PDGFR/PDGF system is essential for the correct development of the kidney, cardiovascular system, brain, lung and connective tissue. In adults, PDGFR/PDGF is important in wound healing, inflammation and angiogenesis. Abnormalities of PDGFR/PDGF are thought to contribute to a number of human diseases, and especially malignancy. Constitutive activation of the PDGFR? or PDGFR? receptor tyrosine kinases is seen in myeloid malignancies as a consequence of fusion to diverse partner genes, and activating mutations of PDGFR? are seen in gastrointestinal tumours (GISTs). Autocrine signalling as a consequence of PDGF-B overexpression is clearly implicated in the pathogenesis of dermatofibrosarcoma protruberans (DFSP) and overexpression of PDGFRs and/or their ligands has been described in many solid tumours. PDGFR signalling is inhibited by imatinib mesylate, and this compound has clear clinical activity in patients with myeloid malignancies, GIST and DFSP
Tyrosine kinase fusion genes in chronic myeloproliferative diseases
No full textWith the exception of chronic myeloid leukemia (CML), chronic myeloproliferative disorders (CMPDs) are a heterogeneous spectrum of conditions for which the molecular pathogenesis is not well understood. Most cases have a normal or aneuploid karyotype, but a minority present with a reciprocal translocation that disrupts specific tyrosine kinase genes, most commonly PDGFRB or FGFR1. These translocations result in the production of constitutively active tyrosine kinase fusion proteins that deregulate hemopoiesis in a manner analogous to BCR-ABL. With the advent of targeted signal transduction therapy, an accurate clinical and molecular diagnosis of CMPDs has become increasingly important. Currently, patients with PDGFRB or ABL fusion genes are candidates for treatment with Imatinib (STI571), but it is likely that alternative strategies will be necessary for the treatment of most other patients
Use of Pyrosequencing technology to quantitate allele expression in patients with BRCA1 mutations
No full textStandardized definitions of molecular response in chronic myeloid leukemia
No full textThe International Randomized Study of Interferon and STI571 (IRIS) study demonstrated long-term cytogenetic responses in patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with the tyrosine kinase inhibitor (TKI) imatinib. However, deep molecular responses (MRs), as measured by reductions in BCR-ABL transcript levels below the threshold of major molecular response (MMR), were achieved only by a small proportion of patients. With the advent of the second-generation TKIs nilotinib and dasatinib for the treatment of patients with newly diagnosed CML-CP, the proportion of patients who achieve the deepest levels of MR is likely to increase significantly. With these changes, the potential for patient eligibility in TKI cessations studies is becoming a more widely discussed topic and area for research. These recent and dramatic shifts in the CML treatment paradigm highlight the need for robust, standardized and workable definitions of deep molecular responses. Specifically, it is critical that the measurement of MR is standardized in a manner to withstand both intra- and inter-laboratory variability as well as new methodological developments. This review summarizes the relevant clinical background and proposes a framework within which standardization of MR can be taken forwar
- …
