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CML RNA sequencing

Li-Di Xu, Marie Öhman
It is well established that somatic mutations and escape of immune disruption are two essential factors in cancer initiation and progression. With an increasing number of second-generation sequencing data, transcriptomic modifications, so called RNA mutations, are emerging as significant forces that drive the transition from normal cell to malignant tumor, as well as providing tumor diversity to escape an immune attack. Editing of adenosine to inosine (A-to-I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome...
December 25, 2018: Genes
Jong-Ho Park, Young Min Woo, Emilia Moonkyung Youm, Nada Hamad, Hong-Hee Won, Kazuhito Naka, Eun-Ju Park, June-Hee Park, Hee-Jin Kim, Sun-Hee Kim, Hyeoung-Joon Kim, Jae Sook Ahn, Sang Kyun Sohn, Joon Ho Moon, Chul Won Jung, Silvia Park, Jeffrey H Lipton, Shinya Kimura, Jong-Won Kim, Dennis Dong Hwan Kim
Achieving a deep molecular response (DMR) to tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) remains challenging and at present, there is no biomarker to predict DMR in this setting. Herein, we report that an HMGCLL1 genetic variant located in 6p12.1 can be used as a predictive genetic biomarker for intrinsic sensitivity to imatinib (IM) therapy. We measured DMR rate according to HMGCLL1 variant in a discovery set of CML patients (n = 201) and successfully replicated it in a validation set (n = 270)...
December 16, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Mary Qu Yang, Sherman M Weissman, William Yang, Jialing Zhang, Allon Canaann, Renchu Guan
BACKGROUND: Single-cell RNA sequencing (scRNA-seq) technology provides an effective way to study cell heterogeneity. However, due to the low capture efficiency and stochastic gene expression, scRNA-seq data often contains a high percentage of missing values. It has been showed that the missing rate can reach approximately 30% even after noise reduction. To accurately recover missing values in scRNA-seq data, we need to know where the missing data is; how much data is missing; and what are the values of these data...
December 14, 2018: BMC Systems Biology
Nuno Cerveira, Rosa Branca Ferreira, Susana Bizarro, Cecília Correia, Lurdes Torres, Susana Lisboa, Joana Vieira, Rui Santos, Fernando Campilho, Carlos Pinho Vaz, Luís Leite, Manuel R Teixeira, António Campos
BACKGROUND: Atypical BCR-ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ-BCR) and coding for the p230 BCR-ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first-line imatinib. CASE PRESENTATION: Here we report a case of imatinib resistance due to an E255V mutation, followed by early post-transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5...
December 7, 2018: BMC Cancer
Kar-Tong Tan, Ling-Wen Ding, Qiao-Yang Sun, Zhen-Tang Lao, Wenwen Chien, Xi Ren, Jin-Fen Xiao, Xin Yi Loh, Liang Xu, Michael Lill, Anand Mayakonda, De-Chen Lin, Henry Yang, H Phillip Koeffler
BACKGROUND: Clonal VDJ rearrangement of B/T cell receptors (B/TCRs) occurring during B/T lymphocyte development has been used as a marker to track the clonality of B/T cell populations. METHODS: We systematically profiled the B/T cell receptor repertoire of 936 cancer cell lines across a variety of cancer types as well as 462 Epstein-Barr Virus (EBV) transformed normal B lymphocyte lines using RNA sequencing data. RESULTS: Rearranged B/TCRs were readily detected in cell lines derived from lymphocytes, and subclonality or potential biclonality were found in a number of blood cancer cell lines...
October 1, 2018: BMC Cancer
Xia Wu, Hadi Kabalane, Malik Kahli, Nataliya Petryk, Bastien Laperrousaz, Yan Jaszczyszyn, Guenola Drillon, Frank-Emmanuel Nicolini, Gaëlle Perot, Aude Robert, Cédric Fund, Frédéric Chibon, Ruohong Xia, Joëlle Wiels, Françoise Argoul, Véronique Maguer-Satta, Alain Arneodo, Benjamin Audit, Olivier Hyrien
The spatiotemporal program of metazoan DNA replication is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replication and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types...
November 2, 2018: Nucleic Acids Research
Sabrina Inselmann, Ying Wang, Susanne Saussele, Lea Fritz, Christin Schütz, Magdalena Huber, Simone Liebler, Thomas Ernst, Dali Cai, Sarah Botschek, Cornelia Brendel, Raffaele A Calogero, Dinko Pavlinic, Vladimir Benes, Edison T Liu, Andreas Neubauer, Andreas Hochhaus, Andreas Burchert
Plasmacytoid dendritic cells (pDC) are the main producers of a key T-cell-stimulatory cytokine, IFNα, and critical regulators of antiviral immunity. Chronic myeloid leukemia (CML) is caused by BCR-ABL, which is an oncogenic tyrosine kinase that can be effectively inhibited with ABL-selective tyrosine kinase inhibitors (TKI). BCR-ABL-induced suppression of the transcription factor interferon regulatory factor 8 was previously proposed to block pDC development and compromise immune surveillance in CML. Here, we demonstrate that pDCs in newly diagnosed CML (CML-pDC) develop quantitatively normal and are frequently positive for the costimulatory antigen CD86...
November 1, 2018: Cancer Research
Ka-Won Kang, Jik-Han Jung, Woojune Hur, Jaena Park, Hyunku Shin, Byeonghyeon Choi, Hyesun Jeong, Dae Sik Kim, Eun Sang Yu, Se Ryeon Lee, Hwa Jung Sung, Seok Jin Kim, Chul Won Choi, Hyun Koo Kim, Sunghoi Hong, Ji-Ho Park, Yeonho Choi, Yong Park, Byung Soo Kim
BACKGROUND/AIM: Exosomes, derived from chronic myelogenous leukaemia (CML) cells, can be used as biomarkers and new targets for the detection of the BCR-ABL transcript. This study aimed to identify these possibilities. MATERIALS AND METHODS: Human CML cell line-derived exosomes and CML-patients-derived exosomes were isolated with a size-exclusion chromatography column and ExoQuick™ exosome precipitation solution, respectively. Isolated exosomes were analysed by nested PCR to detect the BCR-ABL transcript...
July 2018: Anticancer Research
Susan Branford, Paul Wang, David T Yeung, Daniel Thomson, Adrian Purins, Carol Wadham, Nur Hezrin Shahrin, Justine E Marum, Nathalie Nataren, Wendy T Parker, Joel Geoghegan, Jinghua Feng, Naranie Shanmuganathan, Martin C Mueller, Christian Dietz, Doris Stangl, Zoe Donaldson, Haley Altamura, Jasmina Georgievski, Jodi Braley, Anna Brown, Christopher Hahn, Ieuan Walker, Soo-Hyun Kim, Soo-Young Choi, Sa-Hee Park, Dong-Wook Kim, Deborah L White, Agnes S M Yong, David M Ross, Hamish S Scott, Andreas W Schreiber, Timothy P Hughes
Genomic events associated with poor outcome in chronic myeloid leukemia (CML) are poorly understood. We performed whole-exome sequencing, copy-number variation, and/or RNA sequencing for 65 patients to discover mutations at diagnosis and blast crisis (BC). Forty-six patients with chronic-phase disease with the extremes of outcome were studied at diagnosis. Cancer gene variants were detected in 15 (56%) of 27 patients with subsequent BC or poor outcome and in 3 (16%) of 19 optimal responders ( P = .007). Frequently mutated genes at diagnosis were ASXL1 , IKZF1 , and RUNX1 The methyltransferase SETD1B was a novel recurrently mutated gene...
August 30, 2018: Blood
Ziye Li, Lin Yang, Xiaojun Liu, Ziyuan Nie, Jianmin Luo
The long noncoding RNA (lnc) maternally expressed 3 (MEG3) is downregulated in many types of cancers. However, the relationship between lncRNA MEG3, microRNA-21 (miR-21) and chronic myeloid leukemia (CML) blast crisis is unknown. This study examined bone marrow samples from 40 CML patients and 10 healthy donors. Proliferation and apoptosis assays, real-time polymerase chain reaction (PCR), bisulfite sequencing PCR, Western blotting, luciferase assay, RNA pull-down, RNA immunoprecipitation (RIP), co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP) were performed...
August 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Yang Liu, Gui Zhao, Cong-Fei Xu, Ying-Li Luo, Zi-Dong Lu, Jun Wang
Chronic myeloid leukemia (CML), which is characterized by the Philadelphia translocation, which fuses breakpoint cluster region (BCR) sequences from chromosome 22 upstream of the Abelson murine leukemia viral oncogene homolog (ABL) on chromosome 9, requires specific and efficient treatment. The CRISPR/Cas9 system, with its mechanism of specific DNA complementary recognition by engineered guide RNA (gRNA), allows the development of novel therapeutics for CML. To achieve targeted therapy of CML with the CRISPR/Cas9 system, we encapsulated a CRISPR/Cas9 plasmid (pCas9) expressing gRNA targeting the overhanging fusion region of the BCR-ABL gene (pCas9/gBCR-ABL) with poly(ethylene glycol)-b-poly(lactic acid-co-glycolic acid) (PEG-PLGA)-based cationic lipid-assisted polymeric nanoparticles (CLANs), which specifically disrupted the CML-related BCR-ABL gene while sparing the BCR and ABL genes in normal cells...
May 29, 2018: Biomaterials Science
Niklas Landberg, Sofia von Palffy, Maria Askmyr, Henrik Lilljebjörn, Carl Sandén, Marianne Rissler, Satu Mustjoki, Henrik Hjorth-Hansen, Johan Richter, Helena Ågerstam, Marcus Järås, Thoas Fioretos
Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34+ CD38low ) and progenitor (CD34+ CD38+ ) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells...
March 2018: Haematologica
Rebecca Mitchell, Lisa E M Hopcroft, Pablo Baquero, Elaine K Allan, Kay Hewit, Daniel James, Graham Hamilton, Arunima Mukhopadhyay, Jim O'Prey, Alan Hair, Junia V Melo, Edmond Chan, Kevin M Ryan, Véronique Maguer-Satta, Brian J Druker, Richard E Clark, Subir Mitra, Pawel Herzyk, Franck E Nicolini, Paolo Salomoni, Emma Shanks, Bruno Calabretta, Tessa L Holyoake, G Vignir Helgason
Background: Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment...
May 1, 2018: Journal of the National Cancer Institute
Nesreen ALJahdali, Pascale Gadonna-Widehem, Carine Delayre-Orthez, David Marier, Benjamin Garnier, Franck Carbonero, Pauline M Anton
BACKGROUND: Diet is suggested to participate in the etiology of inflammatory bowel diseases (IBD). Repeated exposure to Maillard reaction products (MRPs), molecules resulting from reduction reactions between amino acids and sugars during food heating, has been reported to be either potentially detrimental or beneficial to health. AIMS: The aim of this study is to determine the effect of repeated oral ingestion of N ε -carboxymethyllysine (CML), an advanced MRP, on the onset of two models of experimental IBD and on the gut microbiota composition of mice...
December 2017: Digestive Diseases and Sciences
Alice Giustacchini, Supat Thongjuea, Nikolaos Barkas, Petter S Woll, Benjamin J Povinelli, Christopher A G Booth, Paul Sopp, Ruggiero Norfo, Alba Rodriguez-Meira, Neil Ashley, Lauren Jamieson, Paresh Vyas, Kristina Anderson, Åsa Segerstolpe, Hong Qian, Ulla Olsson-Strömberg, Satu Mustjoki, Rickard Sandberg, Sten Eirik W Jacobsen, Adam J Mead
Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy...
June 2017: Nature Medicine
Xiaokun Zhang, Lin Yang, Xiaojun Liu, Ziyuan Nie, Xingzhe Wang, Yuxia Pan, Jianmin Luo
PTPN6, a tyrosine phosphatase protein, plays a negative role in cell signal transduction and is negatively correlated with tumour formation and growth. However, epigenetic regulation mechanism of the PTPN6 gene in advanced chronic myeloid leukaemia (CML) remains unclear. This study investigated bone marrow or blood samples from 44 CML patients and 10 healthy volunteers. KCL22 and K562 cells were cultured and treated with demethylation drugs and histone deacetylase inhibitors. Real time quantitative polymerase chain reaction (qPCR), methylation-specific PCR, bisulfite sequencing PCR, Western blotting, co-immunoprecipitation and chromatin immunoprecipitation (ChIP) was performed...
September 2017: British Journal of Haematology
H S Madapura, N Nagy, D Ujvari, T Kallas, M C L Kröhnke, S Amu, M Björkholm, L Stenke, P K Mandal, J S McMurray, M Keszei, L S Westerberg, H Cheng, F Xue, G Klein, E Klein, D Salamon
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells...
August 10, 2017: Oncogene
Islem Ben Hassine, Hanene Gharbi, Ismail Soltani, Mouheb Teber, Ahlem Farrah, Hind Ben Hadj Othman, Hassiba Amouri, Hatem Bellaaj, Rayhane Ben Lakhal, Neila Ben Romdhane, Salem Abbes, Samia Menif
PURPOSE: Imatinib mesylate (IM) is considered as a highly effective therapy for chronic myeloid leukemia (CML) patients. However, a minority of patients fail to achieve optimal response due to impaired bioavailability of IM. The human organic cation transporter 1 (OCT1; SLC22A1) has been reported to be the main influx transporter involved in IM uptake into CML cells. Genetic variants and/or hOCT1 expression changes may influence IM response. In this study, we aimed to investigate the impact of both hOCT1 polymorphisms located in exon 7 and hOCT1 mRNA levels on the clinical outcome in CML patients...
April 2017: Cancer Chemotherapy and Pharmacology
Deepak Arya, Sasikala P Sachithanandan, Cecil Ross, Dasaradhi Palakodeti, Shang Li, Sudhir Krishna
The deregulation of lineage control programs is often associated with the progression of haematological malignancies. The molecular regulators of lineage choices in the context of tyrosine kinase inhibitor (TKI) resistance remain poorly understood in chronic myeloid leukemia (CML). To find a potential molecular regulator contributing to lineage distribution and TKI resistance, we undertook an RNA-sequencing approach for identifying microRNAs (miRNAs). Following an unbiased screen, elevated miRNA182-5p levels were detected in Bcr-Abl-inhibited K562 cells (CML blast crisis cell line) and in a panel of CML patients...
January 12, 2017: Cell Death & Disease
Yun Xiao, Changjie Jiao, Yiqiang Lin, Meijun Chen, Jingwen Zhang, Jiajia Wang, Zhongying Zhang
Imatinib (IM) has been applied to the chronic phase of chronic myeloid leukemia (CML) and has great benefit on the prognosis of patients with CML. The function of drug efflux mediated by multidrug resistance protein-1 (MDR1) is considered as a main reason for IM drug resistance in CML cells. However, the exact mechanisms of MDR1 modulation in IM resistance of CML cells remain unclear. In the present study, long noncoding RNA (lncRNA) UCA1 was identified as an important modulator of MDR1 by a model system of leukemia cell lines with a gradual increase of MDR1 expression and IM resistance...
January 2017: DNA and Cell Biology
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