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https://www.readbyqxmd.com/read/28228392/idh-mutant-tumors-vulnerable-to-parp-inhibition
#1
(no author information available yet)
Several cancers, including glioma and acute myeloid leukemia, carry mutations in IDH1 or IDH2 Researchers have found that these mutations impair homologous recombination, making the tumors sensitive to PARP inhibition. They showed that one such inhibitor, olaparib, killed IDH1/2-mutant cancer cells in culture and slowed tumor growth in mice.
February 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28218607/tet2-asxl1-idh1-and-idh2-single-nucleotide-polymorphisms-in-turkish-patients-with-chronic-myeloproliferative-neoplasms
#2
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/28197208/molecular-mutations-and-their-cooccurrences-in-cytogenetically-normal-acute-myeloid-leukemia
#3
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/28193779/combination-targeted-therapy-to-disrupt-aberrant-oncogenic-signaling-and-reverse-epigenetic-dysfunction-in-idh2-and-tet2-mutant-acute-myeloid-leukemia
#4
Alan H Shih, Cem Meydan, Kaitlyn Shank, Francine E Garrett-Bakelman, Patrick S Ward, Andrew Intlekofer, Abbas Nazir, Eytan Stein, Kristina Knapp, Jacob Glass, Jeremy Travins, Kim Straley, Camelia Gliser, Chris Mason, Katharine Yen, Craig B Thompson, Ari Melnick, Ross L Levine
Genomic studies in acute myeloid leukemias (AML) have identified mutations which drive altered DNA methylation, including TET2 and IDH2. Here we show that models of AMLs resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-Azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-Azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output, and resulted in a reduction in leukemic blasts consistent with anti-leukemic activity...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28193778/ag-221-a-first-in-class-therapy-targeting-acute-myeloid-leukemia-harboring-oncogenic-idh2-mutations
#5
Katharine Yen, Jeremy Travins, Fang Wang, Muriel D David, Erin Artin, Kim Straley, Anil Padyana, Stefan Gross, Byron DeLaBarre, Erica Tobin, Yue Chen, Raj Nagaraja, Sung Choe, Lei Jin, Zenon Konteatis, Giovanni Cianchetta, Jeffrey O Saunders, Francesco G Salituro, Cyril Quivoron, Paule Opolon, Olivia Bawa, Véronique Saada, Angelo Paci, Sophie Broutin, Olivier A Bernard, Stéphane de Botton, Benoît S Marteyn, Monika Pilichowska, YingXia Xu, Cheng Fang, Fan Jiang, Wentao Wei, Shengfang Jin, Lee Silverman, Wei Liu, Hua Yang, Lenny Dang, Marion Dorsch, Virginie Penard-Lacronique, Scott A Biller, Shin-San Michael Su
Somatic gain-of-function mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite, (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the Tet family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach...
February 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28161643/sirt3-deacetylated-and-increased-citrate-synthase-activity-in-pd-model
#6
Xin-Xin Cui, Xuan Li, Su-Yan Dong, Yan-Jie Guo, Te Liu, Yun-Cheng Wu
SIRT3 have been found to be neuroprotective in many neurological diseases, but its detail mechanism is only partially understood. In this study, MPP(+) was used to treat SH-SY5Y cells as the cellular model of PD to test the role of SIRT3 and the mechanism may be involved in. We focused on the changes and relationship between SIRT3 and the key mitochondrial enzymes citrate synthase (CS) and isocitrate dehydrogenase 2 (IDH2). We found MPP(+) decreased SIRT3 expression. And our results showed that the enzymatic activities of CS and IDH2 were significantly reduced in MPP(+) treatment cells, while protein acetylation of CS and IDH2 increased...
February 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28157189/identification-of-cell-type-specific-mutations-in-nodal-t-cell-lymphomas
#7
T B Nguyen, M Sakata-Yanagimoto, Y Asabe, D Matsubara, J Kano, K Yoshida, Y Shiraishi, K Chiba, H Tanaka, S Miyano, K Izutsu, N Nakamura, K Takeuchi, H Miyoshi, K Ohshima, T Minowa, S Ogawa, M Noguchi, S Chiba
Recent genetic analysis has identified frequent mutations in ten-eleven translocation 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 2 (IDH2) and ras homolog family member A (RHOA) in nodal T-cell lymphomas, including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified. We examined the distribution of mutations in these subtypes of mature T-/natural killer cell neoplasms to determine their clonal architecture. Targeted sequencing was performed for 71 genes in tumor-derived DNA of 87 cases...
January 6, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28152414/coexisting-and-cooperating-mutations-in-npm1-mutated-acute-myeloid-leukemia
#8
Jay L Patel, Jonathan A Schumacher, Kimberly Frizzell, Shelly Sorrells, Wei Shen, Adam Clayton, Rakhi Jattani, Todd W Kelley
NPM1 insertion mutations represent a common recurrent genetic abnormality in acute myeloid leukemia (AML) patients. The frequency of these mutations varies from approximately 30% overall up to 50% in patients with a normal karyotype. Several recent studies have exploited advances in massively parallel sequencing technology to shed light on the complex genomic landscape of AML. We hypothesize that variant allele fraction (VAF) data derived from massively parallel sequencing studies may provide further insights into the clonal architecture and pathogenesis of NPM1-driven leukemogenesis...
January 23, 2017: Leukemia Research
https://www.readbyqxmd.com/read/28148900/angioimmunoblastic-t-cell-lymphoma-novel-molecular-insights-by-mutation-profiling
#9
Ming Wang, Shaowei Zhang, Shih-Sung Chuang, Margaret Ashton-Key, Eguzkine Ochoa, Niccolo Bolli, George Vassiliou, Zifen Gao, Ming-Qing Du
Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others...
January 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28148839/2-hydroxyglutarate-produced-by-neomorphic-idh-mutations-suppresses-homologous-recombination-and-induces-parp-inhibitor-sensitivity
#10
Parker L Sulkowski, Christopher D Corso, Nathaniel D Robinson, Susan E Scanlon, Karin R Purshouse, Hanwen Bai, Yanfeng Liu, Ranjini K Sundaram, Denise C Hegan, Nathan R Fons, Gregory A Breuer, Yuanbin Song, Ketu Mishra-Gorur, Henk M De Feyter, Robin A de Graaf, Yulia V Surovtseva, Maureen Kachman, Stephanie Halene, Murat Günel, Peter M Glazer, Ranjit S Bindra
2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations, whereas the latter is produced under pathologic processes such as hypoxia. We report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28132785/allosteric-mutant-idh1-inhibitors-reveal-mechanisms-for-idh1-mutant-and-isoform-selectivity
#11
Xiaoling Xie, Daniel Baird, Kimberly Bowen, Vladimir Capka, Jinyun Chen, Gregg Chenail, YoungShin Cho, Julia Dooley, Ali Farsidjani, Pascal Fortin, Darcy Kohls, Raviraj Kulathila, Fallon Lin, Daniel McKay, Lindsey Rodrigues, David Sage, Simon van der Plas, Kirk Wright, Ming Xu, Hong Yin, Julian Levell, Raymond A Pagliarini
Oncogenic IDH1 and IDH2 mutations contribute to cancer via production of R-2-hydroxyglutarate (2-HG). Here, we characterize two structurally distinct mutant- and isoform-selective IDH1 inhibitors that inhibit 2-HG production. Both bind to an allosteric pocket on IDH1, yet shape it differently, highlighting the plasticity of this site. Oncogenic IDH1(R132H) mutation destabilizes an IDH1 "regulatory segment," which otherwise restricts compound access to the allosteric pocket. Regulatory segment destabilization in wild-type IDH1 promotes inhibitor binding, suggesting that destabilization is critical for mutant selectivity...
January 18, 2017: Structure
https://www.readbyqxmd.com/read/28122345/epigenetic-silencing-of-xaf1-in-high-grade-gliomas-is-associated-with-idh1-status-and-improved-clinical-outcome
#12
Thomas R Reich, Olivier J Switzeny, Mirjam Renovanz, Clemens Sommer, Bernd Kaina, Markus Christmann, Maja T Tomicic
XAF1 (X-linked inhibitor of apoptosis (XIAP)-associated factor 1) is a tumor suppressor that counteracts the anti-apoptotic effects of XIAP and can sensitize cells to cell death triggering events. XAF1 knockdown abrogated the temozolomide (TMZ)-induced G2-arrest and prevented TMZ-induced apoptosis in the glioblastoma (GB) cell line LN229. Promoter methylation of XAF1 was found to be inversely correlated with mRNA expression in GB cells. We analyzed XAF1 methylation in a panel of 16 GB cell lines and 80 patients with first-diagnosed WHO grade III/IV high-grade gliomas using methylation-sensitive high-resolution melt (MS-HRM) analysis...
January 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28116838/insular-primary-glioblastomas-with-idh-mutations-clinical-and-biological-specificities
#13
Nobuhiro Hata 秦暢宏, Ryusuke Hatae, Koji Yoshimoto, Hideki Murata, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara
Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations...
January 24, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28106537/down-regulation-of-pseudogene-vimentin-2p-is-associated-with-poor-outcome-in-de-novo-acute-myeloid-leukemia
#14
Ling-Ling Zhai, Jiao Zhou, Jing Zhang, Xi Tang, Ling-Yu Zhou, Jia-Yu Yin, Minse-Evola Deniz Vanessa, Wen Peng, Jiang Lin, Zhao-Qun Deng
OBJECTIVES: This study was intended to investigate the expression status of Vimentin 2p (VIM 2p), a pseudogene of Vimentin, and further analyze its clinical significance in AML patients. METHODS: Real-time quantitative PCR (RQ-PCR) was employed to explore the expression status of VIM 2p in 128 patients with de novo AML and 36 healthy controls. RESULTS: The expression level of VIM 2p was significantly decreased compared with healthy controls (P< 0...
January 13, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28096195/the-multifunctional-mitochondrial-epac1-controls-myocardial-cell-death
#15
Loubina Fazal, Marion Laudette, Sílvia Paula-Gomes, Sandrine Pons, Caroline Conte, Florence Tortosa, Pierre Sicard, Yannis Sainte-Marie, Malik Bisserier, Olivier Lairez, Alexandre Lucas, Jérôme Roy, Bijan Ghaleh, Jeremy Fauconnier, Jeanne Mialet-Perez, Frank Lezoualc'h
RATIONALE: Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood. OBJECTIVE: To investigate the role of mitochondrial exchange protein directly activated by cAMP 1 (MitEpac1) in ischemia/reperfusion (I/R) injury...
January 17, 2017: Circulation Research
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/28052098/idh1-r132h-mutation-enhances-cell-migration-by-activating-akt-mtor-signaling-pathway-but-sensitizes-cells-to-5-fu-treatment-as-nadph-and-gsh-are-reduced
#17
Huixia Zhu, Ye Zhang, Jianfeng Chen, Jiangdong Qiu, Keting Huang, Mindan Wu, Chunlin Xia
AIM OF STUDY: Mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene were recently discovered in vast majority of World Health Organization (WHO) grade II/III gliomas. This study is to understand the effects of IDH1 R132H mutation in gliomagenesis and to develop new strategies to treat glioma with IDH1 R132H mutation. MATERIALS AND METHODS: Over expression of IDH1 R132H in U87MG cells was done by transfecting cells with IDH1 R132H plasmid. MTT assay, scratch repair assay and western blot were performed to study effects of IDH1 R132H mutation on cell proliferation, migration, regulating AKT-mTOR signaling pathway and cell death respectively...
2017: PloS One
https://www.readbyqxmd.com/read/27992414/dynamics-of-clonal-evolution-in-myelodysplastic-syndromes
#18
Hideki Makishima, Tetsuichi Yoshizato, Kenichi Yoshida, Mikkael A Sekeres, Tomas Radivoyevitch, Hiromichi Suzuki, Bartlomiej Przychodzen, Yasunobu Nagata, Manja Meggendorfer, Masashi Sanada, Yusuke Okuno, Cassandra Hirsch, Teodora Kuzmanovic, Yusuke Sato, Aiko Sato-Otsubo, Thomas LaFramboise, Naoko Hosono, Yuichi Shiraishi, Kenichi Chiba, Claudia Haferlach, Wolfgang Kern, Hiroko Tanaka, Yusuke Shiozawa, Inés Gómez-Seguí, Holleh D Husseinzadeh, Swapna Thota, Kathryn M Guinta, Brittney Dienes, Tsuyoshi Nakamaki, Shuichi Miyawaki, Yogen Saunthararajah, Shigeru Chiba, Satoru Miyano, Lee-Yung Shih, Torsten Haferlach, Seishi Ogawa, Jaroslaw P Maciejewski
To elucidate differential roles of mutations in myelodysplastic syndromes (MDS), we investigated clonal dynamics using whole-exome and/or targeted sequencing of 699 patients, of whom 122 were analyzed longitudinally. Including the results from previous reports, we assessed a total of 2,250 patients for mutational enrichment patterns. During progression, the number of mutations, their diversity and clone sizes increased, with alterations frequently present in dominant clones with or without their sweeping previous clones...
February 2017: Nature Genetics
https://www.readbyqxmd.com/read/27991718/polycythemia-vera-and-essential-thrombocythemia-2017-update-on-diagnosis-risk-stratification-and-management
#19
Ayalew Tefferi, Tiziano Barbui
DISEASE OVERVIEW: Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely...
January 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/27983727/the-complexity-of-interpreting-genomic-data-in-patients-with-acute-myeloid-leukemia
#20
A Nazha, A Zarzour, K Al-Issa, T Radivoyevitch, H E Carraway, C M Hirsch, B Przychodzen, B J Patel, M Clemente, S R Sanikommu, M Kalaycio, J P Maciejewski, M A Sekeres
Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of complex genetic alterations responsible for the initiation and progression of the disease. Translating genomic information into clinical practice remained challenging with conflicting results regarding the impact of certain mutations on disease phenotype and overall survival (OS) especially when clinical variables are controlled for when interpreting the result. We sequenced the coding region for 62 genes in 468 patients with secondary AML (sAML) and primary AML (pAML)...
December 16, 2016: Blood Cancer Journal
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