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1.
Daniela Barraco Francesca Carobolante Anna Candoni Erica Simeone Pierpaolo Piccaluga Valentina Tabanelli Renato Fanin 《European journal of haematology》2014,92(6):541-545
Myeloproliferative neoplasms associated with FIP1L1‐PDGFR rearrangements represent a rare subset of myeloid and lymphoid malignancies, characterised by the presence of eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 genes. The fusion product of such genes is a tyrosine kinase oncoprotein sensitive to imatinib, which to date results to be the standard of care for FIP1L1‐PDGFRA‐positive chronic myeloproliferative disorders with eosinophilia. However, the coexistence of FIP1L1‐PDGFRA rearrangement associated with acute myeloid leukaemia is extremely rare. Here, we report a rare case of FIP1L1‐PDGFRA‐positive acute myeloid leukaemia, with marked peripheral blood and bone marrow eosinophilia, treated with low dose of imatinib monotherapy, achieving a rapid and long‐lasting complete cytologic and molecular remission, without need for intensive chemotherapy. 相似文献
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Comparison of high‐resolution melting analysis with direct sequencing for the detection of recurrent mutations in DNA methyltransferase 3A and isocitrate dehydrogenase 1 and 2 genes in acute myeloid leukemia patients
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Patryk Gorniak Anna Ejduk Katarzyna Borg Hanna Makuch‐Lasica Grazyna Nowak Ewa Lech‐Maranda Monika Prochorec‐Sobieszek Krzysztof Warzocha Przemyslaw Juszczynski 《European journal of haematology》2016,96(2):181-187
Acute myeloid leukemia (AML) cells harbor frequent mutations in genes responsible for epigenetic modifications. Increasing evidence of clinical role of DNMT3A and IDH1/2 mutations highlights the need for a robust and inexpensive test to identify these mutations in routine diagnostic work‐up. Herein, we compared routinely used direct sequencing method with high‐resolution melting (HRM) assay for screening DNMT3A and IDH1/2 mutations in patients with AML. We show very high concordance between HRM and Sanger sequencing (100% samples for IDH2‐R140 and DNMT3‐R882 mutations, 99% samples for IDH1‐R132 and IDH2‐R172 mutations). HRM method reported no false‐negative results, suggesting that it can be used for mutations screening. Moreover, HRM displayed much higher sensitivity in comparison with DNA sequencing in all assessed loci. With Sanger sequencing, robust calls were observed when the sample contained 50% of mutant DNA in the background of wild‐type DNA. In marked contrast, the detection limit of HRM improved down to 10% of mutated DNA. Given the ubiquitous presence of wild‐type DNA background in bone marrow aspirates and clonal variations regarding mutant allele burden, these results favor HRM as a sensitive, specific, labor‐, and cost‐effective tool for screening and detection of mutations in IDH1/2 and DNMT3A genes in patients with AML. 相似文献
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Whole‐exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia
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Norio Shiba Kenichi Yoshida Yuichi Shiraishi Yusuke Okuno Genki Yamato Yusuke Hara Yasunobu Nagata Kenichi Chiba Hiroko Tanaka Kiminori Terui Motohiro Kato Myoung‐ja Park Kentaro Ohki Akira Shimada Junko Takita Daisuke Tomizawa Kazuko Kudo Hirokazu Arakawa Souichi Adachi Takashi Taga Akio Tawa Etsuro Ito Keizo Horibe Masashi Sanada Satoru Miyano Seishi Ogawa Yasuhide Hayashi 《British journal of haematology》2016,175(3):476-489
Acute myeloid leukaemia (AML) is a molecularly and clinically heterogeneous disease. Targeted sequencing efforts have identified several mutations with diagnostic and prognostic values in KIT, NPM1, CEBPA and FLT3 in both adult and paediatric AML. In addition, massively parallel sequencing enabled the discovery of recurrent mutations (i.e. IDH1/2 and DNMT3A) in adult AML. In this study, whole‐exome sequencing (WES) of 22 paediatric AML patients revealed mutations in components of the cohesin complex (RAD21 and SMC3), BCORL1 and ASXL2 in addition to previously known gene mutations. We also revealed intratumoural heterogeneities in many patients, implicating multiple clonal evolution events in the development of AML. Furthermore, targeted deep sequencing in 182 paediatric AML patients identified three major categories of recurrently mutated genes: cohesion complex genes [STAG2, RAD21 and SMC3 in 17 patients (8·3%)], epigenetic regulators [ASXL1/ASXL2 in 17 patients (8·3%), BCOR/BCORL1 in 7 patients (3·4%)] and signalling molecules. We also performed WES in four patients with relapsed AML. Relapsed AML evolved from one of the subclones at the initial phase and was accompanied by many additional mutations, including common driver mutations that were absent or existed only with lower allele frequency in the diagnostic samples, indicating a multistep process causing leukaemia recurrence. 相似文献
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A 4‐gene expression score associated with high levels of Wilms Tumor‐1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia
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Ahmadreza Niavarani Tobias Herold Yasmin Reyal Maria C. Sauerland Thomas Buchner Wolfgang Hiddemann Stefan K. Bohlander Peter J. M. Valk Dominique Bonnet 《British journal of haematology》2016,172(3):401-411
Wilms Tumor‐1 (WT1) expression level is implicated in the prognosis of acute myeloid leukaemia (AML). We hypothesized that a gene expression profile associated with WT1 expression levels might be a good surrogate marker. We identified high WT1 gene sets by comparing the gene expression profiles in the highest and lowest quartiles of WT1 expression in two large AML studies. Two high WT1 gene sets were found to be highly correlated in terms of the altered genes and expression profiles. We identified a 17‐probe set signature of the high WT1 set as the optimal prognostic predictor in the first AML set, and showed that it was able to predict prognosis in the second AML series after adjustment for European LeukaemiaNet genetic groups. The gene signature also proved to be of prognostic value in a third AML series of 163 samples assessed by RNA sequencing, demonstrating its cross‐platform consistency . This led us to derive a 4‐gene expression score, which faithfully predicted adverse outcome. In conclusion, a short gene signature associated with high WT1 expression levels and the resultant 4‐gene expression score were found to be predictive of adverse prognosis in AML. This study provides new clues to the molecular pathways underlying high WT1 states in leukaemia. 相似文献
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Multi‐loci diagnosis of acute lymphoblastic leukaemia with high‐throughput sequencing and bioinformatics analysis
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Yann Ferret Aurélie Caillault Shéhérazade Sebda Marc Duez Nathalie Grardel Nicolas Duployez Céline Villenet Martin Figeac Claude Preudhomme Mikaël Salson Mathieu Giraud 《British journal of haematology》2016,173(3):413-420
High‐throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow‐up. As part of an immunoglobulin/T cell receptor‐based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients. 相似文献
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Gelsi-Boyer V Trouplin V Roquain J Adélaïde J Carbuccia N Esterni B Finetti P Murati A Arnoulet C Zerazhi H Fezoui H Tadrist Z Nezri M Chaffanet M Mozziconacci MJ Vey N Birnbaum D 《British journal of haematology》2010,151(4):365-375
Chronic myelomonocytic leukaemia (CMML) is a haematological disease currently classified in the category of myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) because of its dual clinical and biological presentation. The molecular biology of CMML is poorly characterized. We studied a series of 53 CMML samples including 31 cases of myeloproliferative form (MP-CMML) and 22 cases of myelodysplastic forms (MD-CMML) using array-comparative genomic hybridisation (aCGH) and sequencing of 13 candidate genes including ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, PTPN11, RUNX1, TET2 and WT1. Mutations in ASXL1 and in the genes associated with proliferation (CBL, FLT3, PTPN11, NRAS) were mainly found in MP-CMML cases. Mutations of ASXL1 correlated with an evolution toward an acutely transformed state: all CMMLs that progressed to acute phase were mutated and none of the unmutated patients had evolved to acute leukaemia. The overall survival of ASXL1 mutated patients was lower than that of unmutated patients. 相似文献
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Min Shen Idan Menashe Lindsay M. Morton Yawei Zhang Bruce Armstrong Sophia S. Wang Qing Lan Patricia Hartge Mark P. Purdue James R. Cerhan Andrew Grulich Wendy Cozen Meredith Yeager Theodore R. Holford Claire M. Vajdic Scott Davis Brian Leaderer Anne Kricker Richard K. Severson Shelia H. Zahm Nilanjan Chatterjee Nathaniel Rothman Stephen J. Chanock Tongzhang Zheng 《British journal of haematology》2010,151(3):239-244
Genetic variations in DNA repair genes are thought to play an important role in the pathogenesis and development of non‐Hodgkin lymphoma (NHL). To further explore this hypothesis, we genotyped 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions in 1946 cases and 1808 controls pooled from three population‐based case‐control studies of NHL in the US and Australia. Relative risks of NHL and NHL subtypes in relation to SNP genotypes were assessed using logistic regression. Associations of gene regions and pathways with NHL or NHL subtypes were explored using the minP and tail‐strength statistics, respectively. Overall, genetic polymorphisms within the DNA repair pathway were associated with NHL (P = 0·005). Similar associations were seen with the double‐strand break repair (P = 0·02) and nucleotide excision repair (P = 0·04) pathways. Five SNPs (BLM rs441399, RAD50 rs2237060, FAM82A2 rs2304583, ERCC3 rs4150506, and XRCC4 rs13178127) were particularly noteworthy because their gene regions were significantly associated with NHL or NHL subtypes (minP ≤ 0·05), or because of high level of statistical significance (P ≤ 0·005) and consistent findings across the three studies. These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL. 相似文献
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Anti‐leukaemic effects induced by APR‐246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells
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Dina Ali Dara K. Mohammad Huthayfa Mujahed Kerstin Jonson‐Videsäter Beston Nore Christer Paul Sören Lehmann 《British journal of haematology》2016,174(1):117-126
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Cristina Di Genua Maria Jose Larrayoz Nils Winkelmann Paula Aranaz Adam Burns Anna Schuh Maria Jose Calasanz Nicholas C. P. Cross Jacqueline Boultwood 《British journal of haematology》2013,163(2):235-239
Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4·3%), 7 of whom had ?7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression. 相似文献
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Aberrant splicing of genes involved in haemoglobin synthesis and impaired terminal erythroid maturation in SF3B1 mutated refractory anaemia with ring sideroblasts
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Simona Conte Shintaro Katayama Liselotte Vesterlund Mohsen Karimi Marios Dimitriou Monika Jansson Teresa Mortera‐Blanco Per Unneberg Elli Papaemmanuil Birgitta Sander Tiina Skoog Peter Campbell Julian Walfridsson Juha Kere Eva Hellström‐Lindberg 《British journal of haematology》2015,171(4):478-490
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Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double‐strand DNA break repair
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Carolina Alonso‐González Alicia González Carlos Martínez‐Campa José Gómez‐Arozamena Samuel Cos 《Journal of pineal research》2015,58(2):189-197
Radiation and adjuvant endocrine therapy are nowadays considered a standard treatment option after surgery in breast cancer. Melatonin exerts oncostatic actions on human breast cancer cells. In the current study, we investigated the effects of a combination of radiotherapy and melatonin on human breast cancer cells. Melatonin (1 mm , 10 μm and 1 nm ) significantly inhibited the proliferation of MCF‐7 cells. Radiation alone inhibited the MCF‐7 cell proliferation in a dose‐dependent manner. Pretreatment of breast cancer cells with melatonin 1 wk before radiation led to a significantly greater decrease of MCF‐7 cell proliferation compared with radiation alone. Melatonin pretreatment before radiation also decreased G2‐M phase arrest compared with irradiation alone, with a higher percentage of cells in the G0‐G1 phase and a lower percentage of cells in S phase. Radiation alone diminished RAD51 and DNA‐protein kinase (PKcs) mRNA expression, two main proteins involved in double‐strand DNA break repair. Treatment with melatonin for 7 days before radiation led to a significantly greater decrease in RAD51 and DNA?PKcs mRNA expression compared with radiation alone. Our findings suggest that melatonin pretreatment before radiation sensitizes breast cancer cells to the ionizing effects of radiation by decreasing cell proliferation, inducing cell cycle arrest and downregulating proteins involved in double‐strand DNA break repair. These findings may have implications for designing clinical trials using melatonin and radiotherapy. 相似文献
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Kais Hussein Guntram Büsche Michaela Muth Gudrun Göhring Hans Kreipe Oliver Bock 《Annals of hematology》2011,90(3):307-313
The microRNA/miR deregulation in BCR-ABL-negative myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is not known. Myelopoiesis-associated
miR-10a, miR-17-5p, miR-155, miR-223 and miR-424 were analysed by real-time polymerase chain reaction (PCR) in bone marrow
cells of atypical chronic myeloid leukaemia (aCML, n = 7) and chronic myelomonocytic leukaemia (CMML, n = 8) and were compared to BCR-ABL-positive chronic myelogenous leukaemia (CML, n = 10) and non-neoplastic haematopoiesis (n = 10). Down-regulation of miR-10a was found in CMML but also in CML (each p < 0.05, versus controls). Overexpression of miR-424 was detected in aCML (p < 0.05, versus CML and controls). Despite different compositions of bone marrow cells, expression of myelopoiesis-associated
microRNA shows mainly similar patterns in aCML and its main differential diagnosis CMML and does not allow discrimination
of these two MDS/MPN entities. Therefore, the link of deregulated microRNA expression to disease-related phenotype and the
underlying molecular mechanism are still unknown. 相似文献
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Nature and nurture: a case of transcending haematological pre‐malignancies in a pair of monozygotic twins adding possible clues on the pathogenesis of B‐cell proliferations
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Marcus C. Hansen Charlotte G. Nyvold Anne S. Roug Eigil Kjeldsen Palle Villesen Line Nederby Peter Hokland 《British journal of haematology》2015,169(3):391-400
We describe a comprehensive molecular analysis of a pair of monozygotic twins, who came to our attention when one experienced amaurosis fugax and was diagnosed with JAK2+ polycythaemia vera. He (Twin A) was also found to have an asymptomatic B‐cell chronic lymphocytic leukaemia (B‐CLL). Although JAK2?, Twin B was subsequently shown to have a benign monoclonal B‐cell lymphocytosis (MBL). Flow cytometric and molecular analyses of the B‐cell compartments revealed different immunoglobulin light and heavy chain usage in each twin. We hypothesized that whole exome sequencing could help delineating the pattern of germline B‐cell disorder susceptibility and reveal somatic mutations potentially contributing to the differential patterns of pre‐malignancy. Comparing bone marrow cells and T cells and employing in‐house engineered integrative analysis, we found aberrations in Twin A consistent with a myeloid neoplasm, i.e. in TET2, RUNX1, PLCB1 and ELF4. Employing the method for detecting high‐ranking variants by extensive annotation and relevance scoring, we also identified shared germline variants in genes of proteins interacting with B‐cell receptor signalling mediators and the WNT‐pathway, including IRF8, PTPRO, BCL9L, SIT1 and SIRPB1, all with possible implications in B‐cell proliferation. Similar patterns of IGHV‐gene usage to those demonstrated here have been observed in inherited acute lymphoblastic leukaemia. Collectively, these findings may help in facilitating identification of putative master gene(s) involved in B‐cell proliferations in general and MBL and B‐CLL in particular. 相似文献
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Yajing Jiang Ying Li Jingying Cheng Jiao Ma Qinghua Li Tianxiang Pang 《British journal of haematology》2020,189(4):694-706
The leukaemic bone marrow microenvironment, comprising abnormal mesenchymal stromal cells (MSCs), is responsible for the poor prognosis of acute myeloid leukaemia (AML). Therefore, it is essential to determine the mechanisms underlying the supportive role of MSCs in the survival of leukaemia cells. Through in silico analyses, we identified a total of 271 aberrantly expressed genes in the MSCs derived from acute myeloid leukemia (AML) patients that were associated with adipogenic differentiation, of which aldo-keto reductase 1C1 (AKR1C1) was significantly upregulated in the AML-MSCs. Knockdown of AKR1C1 in the MSCs suppressed adipogenesis and promoted osteogenesis, and inhibited the growth of co-cultured AML cell lines compared to the situation in wild- type AML-derived MSCs. Introduction of recombinant human AKR1C1 in the MSCs partially alleviated the effects of AKR1C1 knockdown. In addition, the absence of AKR1C1 reduced secretion of cytokines such as MCP-1, IL-6 and G-CSF from the MSCs, along with inactivation of STAT3 and ERK1/2 in the co-cultured AML cells. AKR1C1 is an essential factor driving the adipogenic differentiation of leukaemic MSCs and mediates its pro-survival effects on AML cells by promoting cytokine secretion and activating the downstream pathways in the AML cells. 相似文献