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https://www.readbyqxmd.com/read/27870387/primary-myelofibrosis-2017-update-on-diagnosis-risk-stratification-and-management
#1
Ayalew Tefferi
: Disease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR or MPL mutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival. DIAGNOSIS: Diagnosis is based on bone marrow morphology...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27849645/current-management-of-patients-with-chronic-myelomonocytic-leukemia
#2
Ana Alfonso, Guillermo Montalban-Bravo, Guillermo Garcia-Manero
PURPOSE OF REVIEW: The present review will focus on the current management of patients with chronic myelomonocytic leukemia (CMML) as well as in future therapeutic perspectives. RECENT FINDINGS: CMML is a clonal hematopoietic stem cell disorder characterized by peripheral blood monocytosis and myelodysplastic and myeloproliferative alterations in the bone marrow. Clinical behavior of the disease can be heterogeneous, with some patients having an indolent form of the disease, whereas others experience an aggressive course with decreased survival and eventual transformation to leukemia...
January 2017: Current Opinion in Oncology
https://www.readbyqxmd.com/read/27777939/tet2-mutations-were-predictive-of-inferior-prognosis-in-the-presence-of-asxl1-mutations-in-patients-with-chronic-myelomonocytic-leukemia
#3
Yajuan Cui, Hongyan Tong, Xin Du, Bing Li, Robert Peter Gale, Tiejun Qin, Jinqin Liu, Zefeng Xu, Yue Zhang, Gang Huang, Jie Jin, Liwei Fang, Hongli Zhang, Lijuan Pan, Naibo Hu, Shiqiang Qu, Zhijian Xiao
BACKGROUND: Somatic mutations involving epigenetic regulators, histone modification and chromatin regulation, splicing components, transcription factors and signaling regulator genes are common in chronic myelomonocytic leukemia (CMML) patients. It has been consensus that ASXL1 mutations have adversely impact on overall survival (OS), while the effect of TET2 mutations remains controversial and undefined. METHODS: ASXL1 and TET2 mutations were analyzed in 141 patients with CMML using Sanger sequencing, with the aim to identify the interplay of ASXL1 and TET2 mutations in the prognosis of CMML...
2016: Stem Cell Investigation
https://www.readbyqxmd.com/read/27766616/genomics-of-primary-chemoresistance-and-remission-induction-failure-in-paediatric-and-adult-acute-myeloid-leukaemia
#4
Fiona C Brown, Paolo Cifani, Esther Drill, Jie He, Eric Still, Shan Zhong, Sohail Balasubramanian, Dean Pavlick, Bahar Yilmazel, Kristina M Knapp, Todd A Alonzo, Soheil Meshinchi, Richard M Stone, Steven M Kornblau, Guido Marcucci, Alan S Gamis, John C Byrd, Mithat Gonen, Ross L Levine, Alex Kentsis
Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases...
October 21, 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27736885/dynamic-asxl1-exon-skipping-and-alternative-circular-splicing-in-single-human-cells
#5
Winston Koh, Veronica Gonzalez, Sivaraman Natarajan, Robert Carter, Patrick O Brown, Charles Gawad
Circular RNAs comprise a poorly understood new class of noncoding RNA. In this study, we used a combination of targeted deletion, high-resolution splicing detection, and single-cell sequencing to deeply probe ASXL1 circular splicing. We found that efficient circular splicing required the canonical transcriptional start site and inverted AluSx elements. Sequencing-based interrogation of isoforms after ASXL1 overexpression identified promiscuous linear splicing between all exons, with the two most abundant non-canonical linear products skipping the exons that produced the circular isoforms...
2016: PloS One
https://www.readbyqxmd.com/read/27736271/asxl1-mutations-are-frequent-in-de-novo-aml-with-trisomy-8-and-confer-an-unfavorable-prognosis
#6
Xiangping Zong, Hong Yao, Lijun Wen, Liang Ma, Qinrong Wang, Zhiluo Yang, Tongtong Zhang, Suning Chen, Wu Depei
No abstract text is available yet for this article.
October 13, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27733013/dnmt3a-mutations-are-associated-with-inferior-overall-and-leukemia-free-survival-in-chronic-myelomonocytic-leukemia
#7
Mrinal M Patnaik, Daniela Barraco, Terra L Lasho, Christy M Finke, Curtis A Hanson, Rhett P Ketterling, Naseema Gangat, Ayalew Tefferi
DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n=261). DNMT3A mutations were seen in 6% (n=16); 56% (n=9) male, with a median age of 64 years. Eighty-one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1-56%, TET2-50%, and ASXL1-25%) were seen in all patients...
October 12, 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27725578/a-primer-for-epigenetics-of-hematological-malignancies
#8
Hideaki Nakajima
Epigenetic marks, such as histone modifications or DNA methylation, regulate tissue specific gene expression by affecting the structures and accessibility of chromatin or DNA. Epigenetics, the molecular mechanisms regulating the epigenome, would therefore be critically involved in development and cell differentiation versus proliferation. Histone modifications include methylation, acetylation, phosphorylation and ubiquitination of specific lysine, arginine or serine residues on histone tails, and each modification has its own specific effect on gene expressions...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27717004/mutations-in-idiopathic-cytopenia-of-undetermined-significance-assist-diagnostics-and-correlate-to-dysplastic-changes
#9
Jakob Werner Hansen, Maj Karoline Westman, Lene Dissing Sjö, Leonie Saft, Lasse Sommer Kristensen, Andreas Due Ørskov, Marianne Treppendahl, Mette Klarskov Andersen, Kirsten Grønbaek
Cytopenia is common in the elderly population and etiology may be difficult to assess. Here, we investigated the occurrence of mutations in patients with idiopathic cytopenia of undetermined significance and the usefulness in improving diagnostics. We included 60 patients with persistent cytopenia > 6 months without definite diagnosis of hematological neoplasm after routine assessment. Bone marrow material underwent a blinded morphology review and DNA was sequenced with a targeted 20 gene panel representing the most commonly mutated genes in myelodysplastic syndrome...
December 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27707735/when-clinical-heterogeneity-exceeds-genetic-heterogeneity-thinking-outside-the-genomic-box-in-chronic-myelomonocytic-leukemia
#10
Markus Ball, Alan F List, Eric Padron
Exome sequencing studies in Chronic Myelomonocytic Leukemia (CMML) illustrate a mutational landscape characterized by few somatic mutations involving a subset of recurrent gene mutations in ASXL1, SRSF2, and TET2, each approaching 40% in incidence. This has led to the clinical implementation of next generation sequencing panels that effectively identify clonal monocytosis and complement clinical prognostic scoring systems in most patients. However, most murine models based on single gene mutations fail to recapitulate the CMML phenotype and many gene mutations are loss-of-function making the identification of traditional therapeutic vulnerabilities challenging...
October 5, 2016: Blood
https://www.readbyqxmd.com/read/27694501/advanced-systemic-mastocytosis-from-molecular-and-genetic-progress-to-clinical-practice
#11
Celalettin Ustun, Michel Arock, Hanneke C Kluin-Nelemans, Andreas Reiter, Wolfgang R Sperr, Tracy George, Hans-Peter Horny, Karin Hartmann, Karl Sotlar, Gandhi Damaj, Olivier Hermine, Srdan Verstovsek, Dean D Metcalfe, Jason Gotlib, Cem Akin, Peter Valent
Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia...
October 2016: Haematologica
https://www.readbyqxmd.com/read/27693232/de-novo-truncating-variants-in-asxl2-are-associated-with-a-unique-and-recognizable-clinical-phenotype
#12
Vandana Shashi, Loren D M Pena, Katherine Kim, Barbara Burton, Maja Hempel, Kelly Schoch, Magdalena Walkiewicz, Heather M McLaughlin, Megan Cho, Nicholas Stong, Scott E Hickey, Christine M Shuss, Michael S Freemark, Jane S Bellet, Martha Ann Keels, Melanie J Bonner, Maysantoine El-Dairi, Megan Butler, Peter G Kranz, Constance T R M Stumpel, Sylvia Klinkenberg, Karin Oberndorff, Malik Alawi, Rene Santer, Slavé Petrovski, Outi Kuismin, Satu Korpi-Heikkilä, Olli Pietilainen, Palotie Aarno, Mitja I Kurki, Alexander Hoischen, Anna C Need, David B Goldstein, Fanny Kortüm
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder...
October 6, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27646892/-characterization-of-mutational-pattern-in-patients-with-ph-negative-myeloproliferative-neoplasms
#13
F Xing, Y N Lin, Q Sun, L Qin, Y J Jia, D L Zhang, K Ru
Objective: To characterize the molecular profile in patients with Ph negative myeloproliferative neoplasms (MPN) by exploring 49 gene mutations. Methods: Targeted gene sequencing were performed to analyze 49 MPN-associated genes in 51 patients with Ph negative MPN, of which CARL (exon 9), NPM1 (exon 12) and CEBPA (TAD, BZIP domains) were investigated by using Sanger sequencing simultaneously, while FLT3-ITD was assessed by PCR method. Results: Mutations were detected in 73.5% (36/49) of genes, and the mutational rates of JAK2-V617F, CALR (exon 9) and MPL were 60...
September 8, 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
https://www.readbyqxmd.com/read/27640403/asxl1-and-jak2v617f-gene-mutation-screening-in-iranian-patients-with-chronic-myeloid-leukemia
#14
Amir Valikhani, Behzad Poopak, Shirin Ferdowsi, Ghasem Azizi Tabesh, Seyed H Ghaffari, Ehsan Saraf Kazeruoni, Negar Rezaei, Alireza Farshchi, Naser Amirizadeh
AIM: In recent years, a few cases of chronic myeloid leukemia (CML) have been reported with both BCR-ABL and JAK2V617F mutations. Moreover, mutations in the additional sex comb-like 1 (ASXL1) gene were recently shown in various myeloid malignancies.There were no previous studies investigating the incidence of the ASXL1 and JAK2V617F mutations in Iranian patients with CML. Consequently, this study focuses on the analysis of these mutations in patients with CML. METHODS: In total, 66 patients with a clinical diagnosis of CML were examined at the time of diagnosis...
September 19, 2016: Asia-Pacific Journal of Clinical Oncology
https://www.readbyqxmd.com/read/27616637/loss-of-asxl1-triggers-an-apoptotic-response-in-human-hematopoietic-stem-and-progenitor-cells
#15
Susan Hilgendorf, Hendrik Folkerts, Jan Jacob Schuringa, Edo Vellenga
ASXL1 is frequently mutated in myelodysplastic syndrome and other hematological malignancies. It has been reported that a loss of ASXL1 leads to a reduction of H3K27me3 via the polycomb repressive complex 2 (PRC2). To determine the role of ASXL1 loss in normal hematopoietic stem and progenitor cells, cord blood CD34(+) cells were transduced with independent small hairpin interfering RNA lentiviral vectors against ASXL1 and cultured under myeloid and erythroid permissive conditions. Knockdown of ASXL1 led to a significant reduction in stem-cell frequency and a reduced cell expansion along the myeloid lineage...
September 8, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27601546/clinical-effects-of-driver-somatic-mutations-on-the-outcomes-of-patients-with-myelodysplastic-syndromes-treated-with-allogeneic-hematopoietic-stem-cell-transplantation
#16
Matteo G Della Porta, Anna Gallì, Andrea Bacigalupo, Silvia Zibellini, Massimo Bernardi, Ettore Rizzo, Bernardino Allione, Maria Teresa van Lint, Pietro Pioltelli, Paola Marenco, Alberto Bosi, Maria Teresa Voso, Simona Sica, Mariella Cuzzola, Emanuele Angelucci, Marianna Rossi, Marta Ubezio, Alberto Malovini, Ivan Limongelli, Virginia V Ferretti, Orietta Spinelli, Cristina Tresoldi, Sarah Pozzi, Silvia Luchetti, Laura Pezzetti, Silvia Catricalà, Chiara Milanesi, Alberto Riva, Benedetto Bruno, Fabio Ciceri, Francesca Bonifazi, Riccardo Bellazzi, Elli Papaemmanuil, Armando Santoro, Emilio P Alessandrino, Alessandro Rambaldi, Mario Cazzola
PURPOSE: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear. PATIENTS AND METHODS: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms...
September 6, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27594918/myb-deregulation-from-a-ewsr1-myb-fusion-at-leukemic-evolution-of-a-jak2-v617f-positive-primary-myelofibrosis
#17
Tiziana Pierini, Danika Di Giacomo, Valentina Pierini, Paolo Gorello, Gianluca Barba, Anair Graciela Lema Fernandez, Fabrizia Pellanera, Tamara Iannotti, Franca Falzetti, Roberta La Starza, Cristina Mecucci
BACKGROUND: Although Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are usually not aggressive, the type and the number of molecular lesions impact greatly on leukemic transformation. Indeed, the molecular background underlying progression is still largely unexplored even though ASXL1, IDH1/2, SRSF2, and TP53 mutations, together with adverse karyotypic changes, place the patient at high risk of leukemic transformation. CASE PRESENTATION: Our patient, a 64-year old man with a diagnosis of JAK2 (V617F) primary myelofibrosis (PMF) had an unusually rapid leukemic transformation...
2016: Molecular Cytogenetics
https://www.readbyqxmd.com/read/27546835/cytogenetic-place-in-managing-myelodysplastic-syndromes-an-update-by-the-groupe-francophone-de-cytog%C3%A3-n%C3%A3-tique-h%C3%A3-matologique-gfch
#18
Virginie Eclache, Marina Lafage-Pochitaloff, Christine Lefebvre, Dominique Penther, Sophie Raynaud, Isabelle Tigaud
The myelodysplastic syndromes (MDS) are preleukemic diseases of elderly patients characterized by defective maturation of clonal hematopoietic progenitor cells resulting in peripheral blood cytopenias. Clonal chromosomal abnormalities are heterogeneous and can be detected in less than 50% of patients with de novo MDS and more frequently in secondary MDS (up to 80%). The karyotype plays an important role in the pathogenesis, diagnosis, and prognosis to evaluate the risk of leukemic transformation and, more recently, in treatment allocation...
October 1, 2016: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/27543316/mutations-of-myelodysplastic-syndromes-mds-an-update
#19
REVIEW
Bani Bandana Ganguly, N N Kadam
The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS...
July 2016: Mutation Research. Reviews in Mutation Research
https://www.readbyqxmd.com/read/27534895/genetic-hierarchy-and-temporal-variegation-in-the-clonal-history-of-acute-myeloid-leukaemia
#20
Pierre Hirsch, Yanyan Zhang, Ruoping Tang, Virginie Joulin, Hélène Boutroux, Elodie Pronier, Hannah Moatti, Pascale Flandrin, Christophe Marzac, Dominique Bories, Fanny Fava, Hayat Mokrani, Aline Betems, Florence Lorre, Rémi Favier, Frédéric Féger, Mohamad Mohty, Luc Douay, Ollivier Legrand, Chrystèle Bilhou-Nabera, Fawzia Louache, François Delhommeau
In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria...
2016: Nature Communications
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