1,721,290 research outputs found
Hitchhikers' guide to the leukemia genome
No full textTKs have been implicated in the pathogenesis of diverse malignancies and often serve as excellent drug targets. Partial mutation scanning of the tyrosine kinome in AML has revealed a paucity of new causative abnormalities in a larger background of previously unknown single-nucleotide polymorphisms and somatically acquired passenger mutations that hitchhike a ride with the malignant clone.<br/
Genomics of myeloproliferative neoplasms
No full textMyeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR-ABL1–negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used
Histone modification defects in developmental disorders and cancer
No full textClinically, Weaver syndrome is closely related to Sotos syndrome, which is frequently caused by mutations in NSD1. This gene also encodes a histone methyltransferase, in this case with activity against histone H3 lysine 36. NSD1 is mutated in carcinoma of the upper aerodigestive tract (www.sanger.ac.uk/genetics/CGP/cosmic/) and also fuses to NUP98 in acute myeloid leukemia. Looking more widely, whole exome screens in lymphoma, multiple myeloma, renal carcinoma and other malignancies have identified genes encoding diverse histone modifiers as targets of somatic mutation. Strikingly, several of these (e.g. MLL2, EP300, CREBBP, ASXL1) are also mutated in human developmental disorders thus pointing towards a remarkable and unexpected convergence between somatic and germline genetic
Standardisation of molecular monitoring for chronic myeloid leukaemia
No full textMolecular monitoring of chronic myeloid leukaemia (CML) patients by real time quantitative reverse transcriptase PCR (RQ-PCR) is of clinical value, but the use of diverse laboratory protocols and units of measurement make it difficult to compare results between and sometimes within centres. This review explores the intrinsic difficulties in standardising the RQ-PCR analysis, summarises the progress that has been made following the proposal for a new International Scale for BCR-ABL measurement and discusses how further improvements are likely to be made.<br/
Chronic myeloproliferative disorders: the role of tyrosine kinases in pathogenesis, diagnosis and therapy
No full textThe term chronic myeloproliferative disorders was originally used by Damashek to describe the link amongst a group of acquired blood diseases. Recent molecular genetic analysis has provided a scientific basis for this observation. Underlying myeloproliferative disorders are acquired abnormalities of tyrosine kinase genes. These may be chromosomal translocations resulting in the creation of a fusion kinase gene, examples of which include ABL, FGFR, and PDGFR as seen in disorders CML, 8p11 myeloproliferative syndrome, atypical CML and chronic eosinophilic leukaemia. The second group of tyrosine kinase abnormalities are point mutations in JAK2, a cytosolic TK. This abnormality is seen in 30-97% of cases of MPD with the phenotype PV, ET or CIM
Molecular pathogenesis of atypical CML, CMML and MDS/MPN-unclassifiable
No full textAccording to the 2008 WHO classification, the category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) includes atypical chronic myeloid leukaemia (aCML), chronic myelomonocytic leukaemia (CMML), MDS/MPN-unclassifiable (MDS/MPN-U), juvenile myelomonocytic leukaemia (JMML) and a “provisional” entity, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T). The remarkable progress in our understanding of the somatic pathogenesis of MDS/MPN has made it clear that there is considerable overlap among these diseases at the molecular level, as well as layers of unexpected complexity. Deregulation of signalling plays an important role in many cases, and is clearly linked to more highly proliferative disease. Other mutations affect a range of other essential, interrelated cellular mechanisms, including epigenetic regulation, RNA splicing, transcription, and DNA damage response. The various combinations of mutations indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. The delineation of complex clonal architectures may serve as the cornerstone for the identification of novel therapeutic targets and lead to better patient outcomes. This review summarizes some of the current knowledge of molecular pathogenetic lesions in the MDS/MPN subtypes that are seen in adults: atypical CML, CMML and MDS/MPN-U
Signal transduction therapy in haematological malignancies: identification and targeting of tyrosine kinases
No full textTyrosine kinases play key roles in cell proliferation, survival and differentiation. Their aberrant activation, caused either by the formation of fusion genes by chromosome translocation or by intragenic changes, such as point mutations or internal duplications, is of major importance in the development of many haematological malignancies. An understanding of the mechanisms by which BCR-ABL contributes to the pathogenesis of chronic myeloid leukaemia led to the development of imatinib, the first of several tyrosine kinase inhibitors to enter clinical trials. Although the development of resistance has been problematic, particularly in aggressive disease, the development of novel inhibitors and combination with other forms of therapy shows promise.Abbreviations: ALK, anaplastic lymphoma kinase; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CEL, chronic eosinophilic leukaemia; CML, chronic myeloid leukaemia; CMML, chronic myelomonocytic leukaemia; EGFR, epidermal growth factor receptor; EMS, Eight p11 myeloproliferative syndrome; EPO, erythropoietin; FGFR, fibroblast growth factor receptor; FIP1L1, Fip1-like 1; FLT3, Fms-like tyrosine kinase 3; FISH, fluorescence in situ hybridization; HES, hypereosinophilic syndrome; IFNa, interferon a; IL3, interleukin 3; IRIS, International Randomized study of Interferon and STI571; ITD, internal tandem duplication; JAK, Janus kinase; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorder; NTRK, neurotrophin receptor kinase; PDGFR, platelet-derived growth factor receptor; Ph, Philadelphia chromosome; PV, polycythaemia vera; RT, reverse transcription; SCT, stem cell transplantation; TK, tyrosine kinase
Genetic and epigenetic complexity in myeloproliferative neoplasms
No full textThe past 7 years have witnessed remarkable progress in our understanding of the genetics of BCR-ABL-negative myeloproliferative neoplasms (MPNs) and has revealed layers of unexpected complexity. Deregulation of JAK2 signaling has emerged as a central feature, but despite having biological activities that recapitulate the cardinal features MPNs in model systems, JAK2 mutations are often secondary events. Several other mutated genes have been identified with a common theme of involvement in the epigenetic control of gene expression. Remarkably, the somatic mutations identified to date do not seem to be acquired in any preferred order, and it is possible that the disease-initiating events remain to be identified. The finding of complex clonal hierarchies in many cases suggests genetic instability that, in principle, may be inherited or acquired. A common haplotype has been identified that is strongly associated with the acquisition of JAK2 mutations, but the cause of relatively high-penetrance familial predisposition to MPNs remains elusive. This review summarizes the established facts relating to the genetics of MPNs, but highlights recent findings and areas of controversy.<br/
Dataset supporting the thesis: Identification of genetic factors associated with myeloid neoplasms
No full textSupplementary tables for Chapter 2,3 and 4 of the PhD Thesis "Identification of genetic factors associated with myeloid neoplasms"</span
Tyrosine kinases as therapeutic targets in BCR-ABL negative chronic myeloproliferative disorders
No full textAcquired constitutive activation of protein tyrosine kinases is a central feature in the pathogenesis of chronic myeloproliferative disorders (CMPDs). The most commonly involved genes are the receptor tyrosine kinases PDGFRA, PDGFRB, FGFR1 or c-KIT and the non-receptor tyrosine kinases JAK2 and ABL. Activation occurs as a consequence of specific point mutations or fusion genes generated by chromosomal translocations, insertions or deletions. Mutant kinases are constitutively active in the absence of the natural ligands resulting in deregulation of haemopoiesis in a manner analogous to BCR-ABL in chronic myeloid leukaemia. With the advent of targeted signal transduction therapy with tyrosine kinase inhibitors, an accurate diagnosis of CMPDs by morphology, karyotyping and molecular genetics has become increasingly important. Imatinib induces high response rates in patients associated with constitutive activation of ABL, PDGFRalpha, PDGFRbeta and some KIT mutants. Other inhibitors under development are promising candidates for effective treatment of patients with constitutive activation of JAK2, FGFR1 and imatinib-resistant KIT mutants
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