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Next generation sequencing leukemia

Samah Nassereddine, Taiga Nishihori, Eric Padron, Rami Mahfouz, Ali Bazarbachi, Rami S Komrokji, Mohamed A Kharfan-Dabaja
Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic neoplastic disorders most commonly occurring in the elderly population; MDS has a tendency to progress to acute leukemia. Although epigenetic therapies have improved the outcomes of MDS patients, allogeneic hematopoietic cell transplantation remains the only curative option. Molecular characterization of MDS using next-generation sequencing has expanded not only the knowledge on MDS but also the depth of understanding of evolution and contribution of recurrent somatic mutations in precursor conditions...
September 16, 2016: Clinical Lymphoma, Myeloma & Leukemia
Cecilia C S Yeung, H Joachim Deeg, Colin Pritchard, David Wu, Min Fang
Jumping translocations (JT) have been identified in numerous malignancies, including leukemia, but infrequently in patients with myelodysplastic syndromes (MDS). The responsible genetic region has been mapped to the JTB gene at 1q21, but breakpoints involving other chromosomal loci, such as 3q and 11q, have been described as well. We have characterized the pathological and mutational landscape, and the clinical course of 6 new MDS patients with jumping mutations using chromosome genomic array testing (CGAT) and target gene panel next generation sequencing...
September 2016: Cancer Genetics
Gera D Te Raa, Arnon P Kater
Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays...
March 2016: Best Practice & Research. Clinical Haematology
G L Uy, E J Duncavage, G S Chang, M A Jacoby, C A Miller, J Shao, S Heath, K Elliott, T Reinick, R S Fulton, C C Fronick, M O'Laughlin, L Ganel, C N Abboud, A F Cashen, J F DiPersio, R K Wilson, D C Link, J S Welch, T J Ley, T A Graubert, P Westervelt, M J Walter
Traditional response criteria in MDS and AML are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (i...
October 14, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Tamara K Moyo, Michael R Savona
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematologic malignancies characterized by a hypercellular bone marrow and morphologic dysplasia in one or more lineage (i.e., myeloid, erythroid, or megakaryocytic), presenting clinically with leukopenia, anemia, and/or thrombocytopenia and with a propensity to transform to acute myelogenous leukemia. Newer technologies such as next-generation sequencing have allowed better understanding of the genetic landscape in MDS. Nearly 80 % of MDS patients have at least one mutation, and approximately 40 recurrent somatic mutations have been identified to occur in >1 % of cases...
October 12, 2016: Current Hematologic Malignancy Reports
Crescenzio Francesco Minervini, Cosimo Cumbo, Paola Orsini, Claudia Brunetti, Luisa Anelli, Antonella Zagaria, Angela Minervini, Paola Casieri, Nicoletta Coccaro, Giuseppina Tota, Luciana Impera, Annamaria Giordano, Giorgina Specchia, Francesco Albano
BACKGROUND: The assessment of TP53 mutational status is becoming a routine clinical practice for chronic lymphocytic leukemia patients (CLL). A broad spectrum of molecular techniques has been employed so far, including both direct Sanger sequencing and next generation sequencing. Oxford Nanopore Technologies recently released the MinION an USB-interfaced sequencer. In this paper we report our experience, with the MinION technology for the detection of the TP53 gene mutation in CLL patients...
October 10, 2016: Diagnostic Pathology
Gian Matteo Rigolin, Elena Saccenti, Cristian Bassi, Laura Lupini, Francesca Maria Quaglia, Maurizio Cavallari, Sara Martinelli, Luca Formigaro, Enrico Lista, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Antonio Urso, Francesco Cavazzini, Massimo Negrini, Antonio Cuneo
No abstract text is available yet for this article.
September 30, 2016: Journal of Hematology & Oncology
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
Justine Ellen Marum, Susan Branford
Molecular monitoring plays an essential role in the clinical management of chronic myeloid leukemia (CML) patients, and now guides clinical decision making. Quantitative reverse-transcriptase-polymerase-chain-reaction (qRT-PCR) assessment of BCR-ABL1 transcript levels has become the standard of care protocol in CML. However, further developments are required to assess leukemic burden more efficiently, monitor minimal residual disease (MRD), detect mutations that drive resistance to tyrosine kinase inhibitor (TKI) therapy and identify predictors of response to TKI therapy...
October 2016: Therapeutic Advances in Hematology
Juli-Anne Gardner, Jason D Peterson, Scott A Turner, Barbara L Soares, Courtney R Lancor, Luciana L Dos Santos, Prabhjot Kaur, Deborah L Ornstein, Gregory J Tsongalis, Francine B de Abreu
OBJECTIVES: To describe three methods used to screen for frameshift mutations in exon 9 of the CALR gene. METHODS: Genomic DNA from 47 patients was extracted from peripheral blood and bone marrow using the EZ1 DNA Blood Kit (Qiagen, Valencia, CA) and quantified by the Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen, San Diego, CA). After clinical history, cytogenetics, and molecular tests, patients were diagnosed with either clonal or nonclonal hematologic diseases...
October 2016: American Journal of Clinical Pathology
Gian Matteo Rigolin, Elena Saccenti, Cristian Bassi, Laura Lupini, Francesca Maria Quaglia, Maurizio Cavallari, Sara Martinelli, Luca Formigaro, Enrico Lista, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Antonio Urso, Francesco Cavazzini, Massimo Negrini, Antonio Cuneo
BACKGROUND: In chronic lymphocytic leukemia (CLL), next-generation sequencing (NGS) analysis represents a sensitive, reproducible, and resource-efficient technique for routine screening of gene mutations. METHODS: We performed an extensive biologic characterization of newly diagnosed CLL, including NGS analysis of 20 genes frequently mutated in CLL and karyotype analysis to assess whether NGS and karyotype results could be of clinical relevance in the refinement of prognosis and assessment of risk of progression...
September 15, 2016: Journal of Hematology & Oncology
Yanjun Sun, Hongjie Shen, Ting Xu, Zhen Yang, Huiying Qiu, Aining Sun, Suning Chen, Depei Wu, Yang Xu
DNMT3A mutations are frequent in cytogenetically normal acute myeloid leukemia (CN-AML) patients and can be present many years before the disease develops. However, the clinical significance of DNMT3A mutation burden in CN-AML remains unclear. In this study, 81 DNMT3A mutated adult CN-AML patients in their first complete remission (CR) were enrolled at our center from March 2005 to May 2015. All patients were identified as having DNMT3A exon 23 mutations, and R882H was the most frequent variant (n=49, 60.49%)...
October 2016: Leukemia Research
Rosalia de Necochea-Campion, Geoffrey P Shouse, Qi Zhou, Saied Mirshahidi, Chien-Shing Chen
The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets...
2016: Journal of Hematology & Oncology
Shuang Fu, Yanping Hu, Yu Fu, Fang Chen, Xuan Liu, Minyu Zhang, Xiaohui Wang, Shichun Tu, Jihong Zhang
Patients with BCR-ABL1 fusion genes are potential candidates for targeted therapy with tyrosine kinase inhibitor (TKI) imatinib. However, novel BCR-ABL1 fusion variants can be undetected by qRT-PCR-based routine molecular screening, affecting immediate patient management and proper treatment selection. In this study, we describe a case of chronic myeloid leukemia (CML) harboring a novel BCR-ABL1 variant gene. Although Fluorescent In situ Hybridization (FISH) analysis suggested Philadelphia (Ph) translocation, qRT-PCR screening failed to detect the presence of a functional fusion transcript, which is critical for selecting targeted therapy against BCR-ABL1 fusion with aberrant kinase activity...
August 12, 2016: Cancer Biology & Therapy
Hanae Sato, Justin C Wheat, Ulrich Steidl, Keisuke Ito
In recent years, advances in next-generation sequencing (NGS) technology have provided the opportunity to detect putative genetic drivers of disease, particularly cancers, with very high sensitivity. This knowledge has substantially improved our understanding of tumor pathogenesis. In hematological malignancies such as acute myeloid leukemia and myelodysplastic syndromes, pioneering work combining multi-parameter flow cytometry and targeted resequencing in leukemia have clearly shown that different classes of mutations appear to be acquired in particular sequences along the hematopoietic differentiation hierarchy...
2016: Frontiers in Oncology
C Mårten Lindqvist, Anders Lundmark, Jessica Nordlund, Eva Freyhult, Diana Ekman, Jonas Carlsson Almlöf, Amanda Raine, Elin Övernäs, Jonas Abrahamsson, Britt-Marie Frost, Dan Grandér, Mats Heyman, Josefine Palle, Erik Forestier, Gudmar Lönnerholm, Eva C Berglund, Ann-Christine Syvänen
To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal...
August 31, 2016: Oncotarget
Richard Rosenquist, Andreas Rosenwald, Ming-Qing Du, Gianluca Gaidano, Patricia Groenen, Andrew Wotherspoon, Paolo Ghia, Philippe Gaulard, Elias Campo, Kostas Stamatopoulos
Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management...
September 2016: Haematologica
Yadong Yang, Nan Ding, Xunong Dong, Xiangdong Fang
Next-generation sequencing technologies have greatly accelerated the biological and medical progression. As one of the applications, miRNA-Seq is invaluable in detecting and characterizing genome-wide miRNAs of either too high or too low abundance. Besides, it can also be used in detecting novel miRNAs. Here, we describe an ab initio analysis of an example chronic myeloid leukemia miRNA sequencing data set to quantify the global expression of miRNAs, detect differential expression and novel miRNAs, and predict target genes...
2016: Methods in Molecular Biology
Maria Ciccone, George Adrian Calin
Chronic lymphocytic leukemia (CLL) is the most common leukemia among adult population in western country. In the last decade, several findings have substantially revolutionized the old concept that CLL is a disease originating from mature, not-dividing cell with indolent clinical course. Notably, next generation sequencing (NGS) have contributed to deepen the knowledge of the cellular networks that imply the onset and the progression of CLL. Among genetic aberrations that are recurrently observed in B-cells from patients with CLL, microRNA deregulation represented the first epigenetic mechanism that has been identified...
August 25, 2016: MicroRNA
S Manteniotis, S Wojcik, P Brauhoff, M Möllmann, L Petersen, J R Göthert, W Schmiegel, U Dührsen, G Gisselmann, H Hatt
The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing...
2016: Cell Death Discovery
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