1,721,114 research outputs found
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/
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
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
How I (diagnose and) treat myeloid / lymphoid neoplasms with tyrosine kinase gene fusions
No full textThe fifth edition of the World Health Organization (WHO) classification and the International Consensus Classification (ICC) both include a category "myeloid/lymphoid neoplasms (MLN) with eosinophilia (eo) and tyrosine kinase (TK) gene fusions” (WHO, MLN-TK; ICC, M/LN-eo-TK). This rare group comprises phenotypically and prognostically heterogeneous disorders, which present a significant diagnostic challenge. The rapid and reliable identification of patients with MLN-TK may be delayed due to genetic complexity and significant phenotypic differences, including the chronic phase and primary/secondary blast phase (BP) of myeloid, lymphoid, or mixed phenotype in the bone marrow (BP-BM) and/or at extramedullary sites (extramedullary disease [EMD]). As a result, the entire armamentarium of conventional molecular genetic and cytogenetic techniques complemented by modern sequencing technologies, such as RNA sequencing or whole-genome sequencing, are often required to identify an underlying TK fusion. TK inhibitors (TKIs) with variable efficacy are available for all fusion genes, but a long-term favorable clinical course under TKI monotherapy is currently only observed in MLN-PDGFRA/PDGFRB fusion genes on imatinib. Because primary/secondary BP-BM/EMD occurs more frequently in MLN-FGFR1/JAK2/FLT3/ETV6::ABL1, a sequential combination of selective TKIs with or without prior intensive chemotherapy, rarely local radiotherapy, and/or subsequent allogeneic hematopoietic cell transplantation should be considered.</p
Redefinition of hypereosinophilic disorders based on an analysis of 28 cases of FIP1L1-PDGFRA negative persistent unexplained eosinophilia (PUE) with eosinophil end-organ damage (EEOD)
No full textIn 1997 the term eosinophil end-organ damage(EEOD) was introduced to facilitate management of patients with high eosinophil counts in whom damage to organs such as heart, lungs, and skin by eosinophils was associated with persistent unexplained eosinophilia (no obvious cause for eosinophilia was identified). In 2003 Cools et al identified the presence of the FIP1L1-PDGFRA gene as the causation of eosinophilia in 50% of cases of hypereosinophilic syndromes with end organ damage. Cases which are negative for this gene and a Tcell clone appear to form a distinctive group whose aetiopathogenesis and clinical significance are different. In order to identify the extent of end organ damage in FIP1L1-PDGFRA negative cases and/or identify rarer causes of unexplained eosinophilia in all cases of eosinophilia presenting from 14.06.2002 to 14.06.2006, we looked at all patients who had persistent eosinophilia present on two separate blood tests done I month apart with eosinophil counts greater than 1–1.5 x 10 9/l. All cases of unexplained eosinophilia (Eosinophil count greater than 1– 1.5 x 10 9/L) seen at our institution in a 4 year period in whom no obvious cause of eosinophilia was found were evaluated for the presence of the FIP1L1-PDGFRA gene, TEL-PDGFRB and variant BCR-ABL gene. Of 40 cases seen 2 men were FIP1L1-PDGFRA positive, 3 others (2 men and 1 woman) had myeloproliferative diseases, I man had clozapine induced eosinophilia, one woman Kimura Weils disease and 1 man had cutaneous mastocytosis . There were 28 cases (14 women, 2 children,12 men) who were FIP1L1 -PDGFRA negative and had persistent unexplained eosinophilia without clonal T cells. These cases were followed up over a 4 year period and tested serially for damage to end organs by eosinophils. FIP1L1-PDGFRA was tested and found negative on two separate occasions. Ig E levels had to be less then 500 iu/l to exclude allergy and a therapeutic trial of mebendazole 100mg daily for three days was given in all cases even if parasite testing did not identify a parasitic infestation. There were 28 cases (14 women, 2 children,12 men) who were FIP1L1-PDGFRA negative which contrasts with the Male Female ratio seen in FIP1 L1-PDGFRA positive cases in which males predominate. The age ranged from 9–80. Four year follow up identified a chronic illness in these cases with no damage to vital organs. Clinical symptoms complained of included fatigue(28), joint and muscle pains(28), skin rashes(10), blackouts(1), thrombotic events(2), diarrhoea(2), fasciitis(2), gastroenteritis(2), cough(2), and breathlessness(2). No organomegaly was seen. In one clonal T cells were identified on serial testing after 1 year of follow up. We conclude that cases of FIP1L1-PDGFRA negative hypereosinophilia are a distinct group with a chronic illness mainly affecting skin and joints who respond well to symptomatic treatment, oral steroids, or hydroxyurea. We believe that hypereosinophilic diorders need to be redined as PUEand EEOD. When both PUE and EEOD are present the diagnosis is HES
Minimal residual disease in chronic myelogenous leukemia: results of RT-PCR detection of BCR-ABL transcripts
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