1,721,042 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/
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
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/
Aberrations of EZH2 in cancer
No full textControl of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2) which catalyses trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases and histone deacetylases resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumours including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity whilst inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors opening up the possibility of refined epigenetic treatments in the future. <br/
Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization
No full textSerial quantification of BCR-ABL1 messenger RNA (mRNA) is an important therapeutic indicator for patients with chronic myeloid leukemia, but historically, there has been substantial variation in results reported by different laboratories. To help improve the comparability of results, an international scale (IS) for BCR-ABL1 was proposed which is being implemented by testing laboratories worldwide. This is being achieved most commonly by the derivation of laboratory-specific conversion factors, but increasingly by the use of kits or reagents that are calibrated to the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL1 mRNA. Recent attention has focused on the need to define and validate levels of deeper molecular response (MR) within the context of the IS. While there has been substantial progress in the alignment of results, BCR-ABL1 measurement is technically challenging and standardization is an ongoing process. <br/
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome
No full textThe 8p11 myeloproliferative syndrome is a rare, aggressive myeloproliferative neoplasm characterised by constitutively active FGFR1 fusion proteins that arise from specificchromosomal translocations and which drive aberrant proliferation. Although FGFR1 inhibitors have shown in vitro activity against FGFR1 fusions, none are in use clinically and there is a need to assess additional compounds as potential therapy. Here we use cell linesand primary cells to investigate ponatinib (AP24534). Ponatinib-treated Ba/F3 cells transformed by ZMYM2-FGFR1 and BCR-FGFR1 and the FGFR1OP2-FGFR1 positiveKG1A cell line showed reduced proliferation and decreased survival when compared to control cells. Inhibition induced apoptosis and reduced phosphorylation of the FGFR1 fusionproteins and substrates. Ponatinib-treated cells from five 8p11 myeloproliferative syndrome patients showed reduced colony growth compared to controls. In one evaluable patient, ponatinib specifically reduced numbers of FGFR1-fusion gene positive colonies. Ponatinib therefore shows considerable promise for the treatment of patients with 8p11myeloproliferative syndrome
Cytogenetics of chronic myeloid leukaemia
No full textThe standard Philadelphia (Ph) translocation t(9;22), its variants and a proportion of Ph-negative cases are positive for the BCR-ABL fusion gene, as determined by molecular analysis. Extensive deletions of chromosome 9 and 22 derived sequences around the translocation breakpoints on the derivative 9 are seen in 10–30% of patients at diagnosis and may confer a worse prognosis. Additional cytogenetic changes can occur in the few months before or during disease progression and are often specific for blast morphology; however, the molecular basis of the most common additional cytogenetic abnormalities is largely unknown. Cytogenetics is important for monitoring patient response to treatment but is increasingly being replaced by the more sensitive and less invasive techniques of RT-PCR and FISH
Quantitative analysis of SNRPN [correction of SRNPN] gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome
No full textBackground: Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (70%) or maternal uniparental disomy (UPD; 30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (70%) or by paternal UPD (5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS.Methods: Sodium bisulfite–treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol.Results: The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol.Conclusions: Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS
Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations
No full textMosaic loss of the Y-chromosome (LOY) is the most common somatic alteration in men. We aimed to assess the relationship between LOY and serum biomarkers in UK Biobank and explore the interaction with constitutional and somatic genetics. LOY was strongly associated with levels of sex hormone binding globulin (SHBG, β=0.12, PFDR= P = 7.44×10−36, adjusted for age, age squared, gender, smoking status, smoking intensity and principal genetic components), a key regulator of testosterone bioavailability associated with diverse disorders including cancer and autoimmune diseases. Furthermore, LOY was associated with total testosterone (TT, β=0.09, PFDR=2.23 × 10−20), but not bioavailable testosterone (PFDR=0.46) or free testosterone (PFDR=0.75). These relationships remained significant after sensitivity analysis that included comorbidities and body mass index (SHBG, β = 0.08, PFDR = 4.61×10−21; TT, β = 0.05, PFDR = 4.13 × 10−9). Mendelian randomisation suggested a causal effect of SHBG on LOY in BioBank Japan (P=6.58×10−4) but there was no evidence for an effect of LOY on SHBG (P=0.46). Assessment of cis-eQTLs for 13 genes associated with LOY identified two SNPs that were also associated with levels of SHBG, however only rs7141210 (imprinted DLK1-MEG3 locus) modified the relationship between SHBG and LOY (rs7141210-T/T; Pinteraction=0.04) with low levels of SHBG seen specifically in men without LOY (β=-0.02, P=0.001), but not those with LOY (P=0.41). Age-related clonal hematopoiesis (CH) defined by somatic driver mutations was not associated with sex hormone levels but was associated with LOY at clonal fractions >30% (OR=1.52, P=2.92×10−4). TET2, TP53, and CBL mutations were enriched in high level LOY cases, but not DNMT3A or ASXL1. Our findings thus identify independent relationships between LOY, sex hormones and CH
Myeloproliferative disorders
No full textThe myeloproliferative disorders (MPDs) are a group of pre-leukaemic disorders characterized by proliferation of one or more lineages of the myelo-erythroid series. Unlike the Philadelphia chromosome in chronic myeloid leukaemia, there is no pathognomonic chromosomal abnormality associated with the MPDs. Chromosomal abnormalities are seen in 30–40% of patients with polycythaemia vera (PV) and idiopathic myelofibrosis (IMF) and seem to indicate a poor prognosis. On the other hand, chromosomal abnormalities are rare in essential thrombocythaemia. Consistent acquired changes seen at diagnosis include deletion of the long arm of chromosome 20, del(13q), trisomy 8 and 9 and duplication of parts of 1q. Furthermore del(20q), trisomy 8 and dupl(lq) all arise in multipotent progenitor cells. Molecular mapping of 20q deletions and, to some extent, 13q deletions has identified a number of candidate target genes, although no mutations have yet been found. Finally, translocations associated with the rare 8p11 myeloproliferative syndrome and other atypical myeloproliferative disorders have permitted the identification of a number of novel fusion proteins involving fibroblast growth factor receptor-1
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