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https://www.readbyqxmd.com/read/28335073/clinical-characteristics-and-whole-exome-transcriptome-sequencing-of-coexisting-chronic-myeloid-leukemia-and-myelofibrosis
#1
Malathi Kandarpa, Yi-Mi Wu, Dan Robinson, Patrick William Burke, Arul M Chinnaiyan, Moshe Talpaz
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell (HSC) disorders that can be classified on the basis of genetic, clinical, phenotypic features. Genetic lesions such as JAK2 mutations and BCR-ABL translocation are often mutually exclusive in MPN patients and lead to essential thrombocythemia, polycythemia vera or myelofibrosis (ET/PV/MF) or chronic myeloid leukemia, respectively. Nevertheless, coexistence of these genetic aberrations in the same patient has been reported. Whether these aberrations occur in the same stem cell or a different cell is unclear, but an unstable genome in the HSCs seems to be the common antecedent...
March 23, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28314085/targeted-next-generation-sequencing-and-identification-of-risk-factors-in-world-health-organization-defined-atypical-chronic-myeloid-leukemia
#2
Mrinal M Patnaik, Daniela Barraco, Terra L Lasho, Christy M Finke, Kaaren Reichard, Katherine P Hoversten, Rhett P Ketterling, Naseema Gangat, Ayalew Tefferi
Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8% and PTPN11 4%...
March 17, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28297624/genomics-of-acute-myeloid-leukemia-diagnosis-and-pathways
#3
Lars Bullinger, Konstanze Döhner, Hartmut Döhner
In recent years, our understanding of the molecular pathogenesis of myeloid neoplasms, including acute myeloid leukemia (AML), has been greatly advanced by genomics discovery studies that use novel high-throughput sequencing techniques. AML, similar to most other cancers, is characterized by multiple somatically acquired mutations that affect genes of different functional categories, a complex clonal architecture, and disease evolution over time. Patterns of mutations seem to follow specific and temporally ordered trajectories...
March 20, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28273187/-the-role-of-driver-and-subclonal-mutations-in-pathogenesis-of-primary-myelofibrosis
#4
Réka Mózes, Ambrus Gángó, Zsófia Boha, Judit Csomor, Csaba Bödör
Primary myelofibrosis (PMF) is a Philadelphia chromosome negative, clonal myeloproliferative neoplasm characterised by a progressive nature. Morphologically, the bone marrow biopsy shows features of abnormal proliferation of terminally differentiated megakaryocytes and subsequent bone marrow fibrosis. The molecular landscape of PMF includes phenotypic driver mutations (JAK2 V617F, CALR and MPL) which represent major diagnostic criteria, and subclonal mutations that also occur in several other myeloid diseases, but have a prognostic value in disease progression of MF...
March 8, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28255023/the-clinical-and-molecular-diversity-of-mast-cell-leukemia-with-or-without-associated-hematologic-neoplasm
#5
Mohamad Jawhar, Juliana Schwaab, Manja Meggendorfer, Nicole Naumann, Hans-Peter Horny, Karl Sotlar, Torsten Haferlach, Karla Schmitt, Alice Fabarius, Peter Valent, Wolf-Karsten Hofmann, Nicholas C P Cross, Georgia Metzgeroth, Andreas Reiter
Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by ≥20% mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16/28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12/28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 565 microg/L...
March 2, 2017: Haematologica
https://www.readbyqxmd.com/read/28229513/pathogenic-asxl1-somatic-variants-in-reference-databases-complicate-germline-variant-interpretation-for-bohring-opitz-syndrome
#6
Colleen M Carlston, Anne H O'Donnell-Luria, Hunter R Underhill, Beryl B Cummings, Ben Weisburd, Eric V Minikel, Daniel P Birnbaum, Tatiana Tvrdik, Daniel G MacArthur, Rong Mao
The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a six-year-old female patient with seizures, developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant previously reported as causative of Bohring-Opitz syndrome (BOS)...
February 23, 2017: Human Mutation
https://www.readbyqxmd.com/read/28219221/-the-clinical-characteristics-gene-mutations-and-prognosis-of-chronic-neutrophilic-leukemia
#7
Y J Cui, Q Jiang, J Q Liu, B Li, Z F Xu, T J Qin, Y Zhang, W Y Cai, H L Zhang, L W Fang, L J Pan, N B Hu, S Q Qu, Z J Xiao
Objective: To investigate the clinical manifestation, cytogenetics, gene mutations and prognostic factors of chronic neutrophilic leukemia (CNL) . Methods: 16 CNL cases, according to WHO (2016) -definition, were reviewed retrospectively. Identifications of the CSF3R, ASXL1, SETBP1, CALR and MPL mutations were performed by direct sequencing. JAK2 V617F mutation was detected by AS-PCR. Results: Of the 16 CNL patients, the median age was 64 (43-80) years with a male predominance of 75% (12/16) . The median hemoglobin was 114 (81-154) g/L, with median WBC of 41...
January 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28218607/tet2-asxl1-idh1-and-idh2-single-nucleotide-polymorphisms-in-turkish-patients-with-chronic-myeloproliferative-neoplasms
#8
Nur Soyer, Burçin Tezcanlı Kaymaz, Melda Cömert Özkan, Çağdaş Aktan, Ali Şahin Küçükaslan, Fahri Şahin, Buket Kosova, Güray Saydam
We aimed to determine the genotype distribution, allele frequency and prognostic impact of IDH1/2(Isocitrate dehydrogenase), TET2(Ten-Eleven-Translocation2) and ASXL1(Additional Sex Combs-Like 1) single nucleotide polymorphisms (SNPs) in MPNs. TET2(rs763480), ASXL1(rs2208131) and IDH1(rs11554137) variant homozygous genotype frequencies were 1.5%, 9.2% and 2.3%, respectively. No IDH2 SNP was identified. IDH1 and TET2 frequencies were 5% in ET and 1.7% in ET, 5% in PMF, respectively. ASXL1 frequencies were 8...
February 20, 2017: Turkish Journal of Haematology: Official Journal of Turkish Society of Haematology
https://www.readbyqxmd.com/read/28211153/the-prognostic-relevance-of-serum-lactate-dehydrogenase-and-mild-bone-marrow-reticulin-fibrosis-in-essential-thrombocythemia
#9
Mythri Mudireddy, Daniela Barraco, Curtis A Hanson, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
The 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the prognostically-relevant distinction between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF). In addition, leukocytosis has been identified as an important prognostic marker in otherwise WHO-defined ET. However, controversy remains regarding the objectivity of morphologic criteria in distinguishing ET from pre-PMF and the precise prognostic cutoff values for leukocytosis...
February 17, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#10
REVIEW
Mengning Wang, Chuanwei Yang, Le Zhang, Dale G Schaar
Adult acute myeloid leukemia (AML) clinically is a disparate disease that requires intensive treatments ranging from chemotherapy alone to allogeneic hematopoietic cell transplantation (allo-HCT). Historically, cytogenetic analysis has been a useful prognostic tool to classify patients into favorable, intermediate, and unfavorable prognostic risk groups. However, the intermediate-risk group, consisting predominantly of cytogenetically normal AML (CN-AML), itself exhibits diverse clinical outcomes and requires further characterization to allow for more optimal treatment decision-making...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28188970/refractory-anemia-with-ring-sideroblasts-rars-and-rars-with-thrombocytosis-rars-t-2017-update-on-diagnosis-risk-stratification-and-management
#11
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T). DIAGNOSIS: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations)...
March 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28116354/asxl1-interacts-with-the-cohesin-complex-to-maintain-chromatid-separation-and-gene-expression-for-normal-hematopoiesis
#12
Zhaomin Li, Peng Zhang, Aimin Yan, Zhengyu Guo, Yuguang Ban, Jin Li, Shi Chen, Hui Yang, Yongzheng He, Jianping Li, Ying Guo, Wen Zhang, Ehsan Hajiramezanali, Huangda An, Darlene Fajardo, J William Harbour, Yijun Ruan, Stephen D Nimer, Peng Yu, Xi Chen, Mingjiang Xu, Feng-Chun Yang
ASXL1 is frequently mutated in a spectrum of myeloid malignancies with poor prognosis. Loss of Asxl1 leads to myelodysplastic syndrome-like disease in mice; however, the underlying molecular mechanisms remain unclear. We report that ASXL1 interacts with the cohesin complex, which has been shown to guide sister chromatid segregation and regulate gene expression. Loss of Asxl1 impairs the cohesin function, as reflected by an impaired telophase chromatid disjunction in hematopoietic cells. Chromatin immunoprecipitation followed by DNA sequencing data revealed that ASXL1, RAD21, and SMC1A share 93% of genomic binding sites at promoter regions in Lin(-)cKit(+) (LK) cells...
January 2017: Science Advances
https://www.readbyqxmd.com/read/28107566/recent-advances-in-understanding-clonal-haematopoiesis-in-aplastic-anaemia
#13
REVIEW
Natasha Stanley, Timothy S Olson, Daria V Babushok
Acquired aplastic anaemia (AA) is an immune-mediated bone marrow failure disorder inextricably linked to clonal haematopoiesis. The majority of AA patients have somatic mutations and/or structural chromosomal abnormalities detected as early as at diagnosis. In contrast to other conditions linked to clonal haematopoiesis, the clonal signature of AA reflects its immune pathophysiology. The most common alterations are clonal expansions of cells lacking glycophosphotidylinositol-anchored proteins, loss of human leucocyte antigen alleles, and mutations in BCOR/BCORL1, ASXL1 and DNMT3A...
January 20, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28097878/focusing-on-frequent-asxl1-mutations-in-myeloid-neoplasms-and-considering-rarer-asxl2-and-asxl3-mutations
#14
Jean S Oak, Robert S Ohgami
No abstract text is available yet for this article.
February 3, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28076841/clonal-evolution-in-therapy-related-neoplasms
#15
Emiliano Fabiani, Giulia Falconi, Luana Fianchi, Marianna Criscuolo, Tiziana Ottone, Laura Cicconi, Stefan Hohaus, Simona Sica, Massimiliano Postorino, Antonino Neri, Marta Lionetti, Giuseppe Leone, Francesco Lo-Coco, Maria Teresa Voso
Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28070990/a-targeted-next-generation-sequencing-in-the-molecular-risk-stratification-of-adult-acute-myeloid-leukemia-implications-for-clinical-practice
#16
Po-Han Lin, Huei-Ying Li, Sheng-Chih Fan, Tzu-Hang Yuan, Ming Chen, Yu-Hua Hsu, Yu-Hsuan Yang, Long-Yuan Li, Su-Peng Yeh, Li-Yuan Bai, Yu-Min Liao, Chen-Yuan Lin, Ching-Yun Hsieh, Ching-Chan Lin, Che-Hung Lin, Ming-Yu Lien, Tzu-Ting Chen, Yen-Hsuan Ni, Chang-Fang Chiu
Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable-risk groups; however, patients with intermediate-risk cytogenetics represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next-generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1(mutation) /FLT3- internal tandem duplication (ITD)(negative) were independent prognostic factors for the entire cohort...
February 2017: Cancer Medicine
https://www.readbyqxmd.com/read/28063196/asxl2-mutations-are-frequently-found-in-pediatric-aml-patients-with-t-8-21-runx1-runx1t1-and-associated-with-a-better-prognosis
#17
Genki Yamato, Norio Shiba, Kenichi Yoshida, Yuichi Shiraishi, Yusuke Hara, Kentaro Ohki, Jun Okubo, Haruna Okuno, Kenichi Chiba, Hiroko Tanaka, Akitoshi Kinoshita, Hiroshi Moritake, Nobutaka Kiyokawa, Daisuke Tomizawa, Myoung-Ja Park, Manabu Sotomatsu, Takashi Taga, Souichi Adachi, Akio Tawa, Keizo Horibe, Hirokazu Arakawa, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
ASXL2 is an epigenetic regulator involved in polycomb repressive complex regulation or recruitment. Clinical features of pediatric acute myeloid leukemia (AML) patients with ASXL2 mutations remain unclear. Thus, we investigated frequencies of ASXL1 and ASXL2 mutations, clinical features of patients with these mutations, correlations of these mutations with other genetic alterations including BCOR/BCORL1 and cohesin complex component genes, and prognostic impact of these mutations in 369 pediatric patients with de novo AML (0-17 years)...
May 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28058097/genetics-and-epigenetics-of-myelodysplastic-syndromes-and-response-to-drug-therapy-new-insights
#18
REVIEW
Saeid Shahrabi, Abbas Khosravi, Mohammad Shahjahani, Fakher Rahim, Najmaldin Saki
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms ocurring mostly in the elderly. The clinical outcome of MDS patients is still poor despite progress in treatment approaches. About 90% of patients harbor at least one somatic mutation. This review aimed to assess the potential of molecular abnormalities in understanding pathogenesis, prognosis, diagnosis and in guiding choice of proper therapy in MDS patients. Papers related to this topic from 2000 to 2016 in PubMed and Scopus databases were searched and studied...
October 10, 2016: Oncology Reviews
https://www.readbyqxmd.com/read/28055972/integrative-genomic-and-transcriptomic-analysis-for-pinpointing-recurrent-alterations-of-plant-homeodomain-genes-and-their-clinical-significance-in-breast-cancer
#19
Huimei Yu, Yuanyuan Jiang, Lanxin Liu, Wenqi Shan, Xiaofang Chu, Zhe Yang, Zeng-Quan Yang
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients...
December 31, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028029/genetic-basis-and-molecular-pathophysiology-of-classical-myeloproliferative-neoplasms
#20
REVIEW
William Vainchenker, Robert Kralovics
The genetic landscape of classical myeloproliferative neoplasm (MPN) is in large part elucidated. The MPN-restricted driver mutations, including those in JAK2, calreticulin (CALR), and myeloproliferative leukemia virus (MPL), abnormally activate the cytokine receptor/JAK2 pathway and their downstream effectors, more particularly the STATs. The most frequent mutation, JAK2V617F, activates the 3 main myeloid cytokine receptors (erythropoietin receptor, granulocyte colony-stimulating factor receptor, and MPL) whereas CALR or MPL mutants are restricted to MPL activation...
February 9, 2017: Blood
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