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Oncogenic mutations

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https://www.readbyqxmd.com/read/28213513/runx1-cooperates-with-flt3-itd-to-induce-leukemia
#1
Kira Behrens, Katrin Maul, Nilgün Tekin, Neele Kriebitzsch, Daniela Indenbirken, Vladimir Prassolov, Ursula Müller, Hubert Serve, Jörg Cammenga, Carol Stocking
Acute myeloid leukemia (AML) is induced by the cooperative action of deregulated genes that perturb self-renewal, proliferation, and differentiation. Internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase are common mutations in AML, confer poor prognosis, and stimulate myeloproliferation. AML patient samples with FLT3-ITD express high levels of RUNX1, a transcription factor with known tumor-suppressor function. In this study, to understand this paradox, we investigated the impact of RUNX1 and FLT3-ITD coexpression...
February 17, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28213501/immature-lymphocytes-inhibit-rag1-and-rag2-transcription-and-v-d-j-recombination-in-response-to-dna-double-strand-breaks
#2
Megan R Fisher, Adrian Rivera-Reyes, Noah B Bloch, David G Schatz, Craig H Bassing
Mammalian cells have evolved a common DNA damage response (DDR) that sustains cellular function, maintains genomic integrity, and suppresses malignant transformation. In pre-B cells, DNA double-strand breaks (DSBs) induced at Igκ loci by the Rag1/Rag2 (RAG) endonuclease engage this DDR to modulate transcription of genes that regulate lymphocyte-specific processes. We previously reported that RAG DSBs induced at one Igκ allele signal through the ataxia telangiectasia mutated (ATM) kinase to feedback-inhibit RAG expression and RAG cleavage of the other Igκ allele...
February 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28213331/mitochondrial-metabolism-and-energy-sensing-in-tumor-progression
#3
REVIEW
Luisa Iommarini, Anna Ghelli, Giuseppe Gasparre, Anna Maria Porcelli
Energy homeostasis is pivotal for cell fate since metabolic regulation, cell proliferation and death are strongly dependent on the balance between catabolic and anabolic pathways. In particular, metabolic and energetic changes have been observed in cancer cells even before the discovery of oncogenes and tumor suppressors, but has been neglected for a long time. Instead, during the past 20years a renaissance of the study of tumor metabolism has led to a revised and more accurate sight of the metabolic landscape of cancer cells...
February 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28212429/the-p53-isoform-delta133p53%C3%A3-regulates-cancer-cell-apoptosis-in-a-rhob-dependent-manner
#4
Nikola Arsic, Alexandre Ho-Pun-Cheung, Crapez Evelyne, Eric Assenat, Marta Jarlier, Christelle Anguille, Manon Colard, Mikaël Pezet, Pierre Roux, Gilles Gadea
The TP53 gene plays essential roles in cancer. Conventionally, wild type (WT) p53 is thought to prevent cancer development and metastasis formation, while mutant p53 has transforming abilities. However, clinical studies failed to establish p53 mutation status as an unequivocal predictive or prognostic factor of cancer progression. The recent discovery of p53 isoforms that can differentially regulate cell cycle arrest and apoptosis suggests that their expression, rather than p53 mutations, could be a more clinically relevant biomarker in patients with cancer...
2017: PloS One
https://www.readbyqxmd.com/read/28209747/pediatric-adolescent-and-young-adult-thyroid-carcinoma-harbors-frequent-and-diverse-targetable-genomic-alterations-including-kinase-fusions
#5
Pierre Vanden Borre, Alexa B Schrock, Peter M Anderson, John C Morris, Andreas M Heilmann, Oliver Holmes, Kai Wang, Adrienne Johnson, Steven G Waguespack, Sai-Hong Ignatius Ou, Saad Khan, Kar-Ming Fung, Philip J Stephens, Rachel L Erlich, Vincent A Miller, Jeffrey S Ross, Siraj M Ali
BACKGROUND: Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. METHODS: Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements...
February 16, 2017: Oncologist
https://www.readbyqxmd.com/read/28209658/relevance-of-id3-tcf3-ccnd3-pathway-mutations-in-pediatric-aggressive-b-cell-lymphoma-treated-according-to-the-nhl-bfm-protocols
#6
Marius Rohde, Bettina R Bonn, Martin Zimmermann, Jonas Lange, Anja Möricke, Wolfram Klapper, Ilske Oschlies, Monika Szczepanowski, Inga Nagel, Martin Schrappe, Markus Loeffler, Reiner Siebert, Alfred Reiter, Birgit Burkhardt
Mature B-cell Non-Hodgkin lymphoma is the most common subtype of Non-Hodgkin lymphoma in childhood and adolescence. B-cell Non-Hodgkin lymphoma are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient hit for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell Non-Hodgkin lymphoma patients...
February 16, 2017: Haematologica
https://www.readbyqxmd.com/read/28208660/splice-variants-of-the-rtk-family-their-role-in-tumour-progression-and-response-to-targeted-therapy
#7
REVIEW
Cherine Abou-Fayçal, Anne-Sophie Hatat, Sylvie Gazzeri, Beatrice Eymin
Receptor tyrosine kinases (RTKs) belong to a family of transmembrane receptors that display tyrosine kinase activity and trigger the activation of downstream signalling pathways mainly involved in cell proliferation and survival. RTK amplification or somatic mutations leading to their constitutive activation and oncogenic properties have been reported in various tumour types. Numerous RTK-targeted therapies have been developed to counteract this hyperactivation. Alternative splicing of pre-mRNA has recently emerged as an important contributor to cancer development and tumour maintenance...
February 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28208123/analysis-of-acquired-mutations-in-transgenes-arising-in-ba-f3-transformation-assays-findings-and-recommendations
#8
Kevin Watanabe-Smith, Jamila Godil, Anupriya Agarwal, Cristina Tognon, Brian Druker
The identification and functional validation of potentially oncogenic mutations in leukemia is an essential step toward a future of personalized targeted therapy. To assess the oncogenic capacity of individual mutations, reliable and scalable in vitro experimental approaches are required. Since 1988, researchers have used the IL-3 dependent Ba/F3 transformation assay to validate the oncogenic potential of mutations to drive factor-independent growth. Here we report a previously unrecognized phenomenon whereby Ba/F3 cells, engineered to express weakly transforming mutations, present with additional acquired mutations in the expressed transgene following factor withdrawal...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28202525/oncogenic-effects-of-high-mapk-activity-in-colorectal-cancer-mark-progenitor-cells-and-persist-irrespective-of-ras-mutations
#9
Cristina Blaj, Eva Marina Schmidt, Sebastian Lamprecht, Heiko Hermeking, Andreas Jung, Thomas Kirchner, David Horst
About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling which promotes tumor invasion and progression. Here we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202506/recurrent-patterns-of-dna-copy-number-alterations-in-tumors-reflect-metabolic-selection-pressures
#10
Nicholas A Graham, Aspram Minasyan, Anastasia Lomova, Ashley Cass, Nikolas G Balanis, Michael Friedman, Shawna Chan, Sophie Zhao, Adrian Delgado, James Go, Lillie Beck, Christian Hurtz, Carina Ng, Rong Qiao, Johanna Ten Hoeve, Nicolaos Palaskas, Hong Wu, Markus Müschen, Asha S Multani, Elisa Port, Steven M Larson, Nikolaus Schultz, Daniel Braas, Heather R Christofk, Ingo K Mellinghoff, Thomas G Graeber
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including (18)F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation...
February 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#11
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28199202/racial-disparity-in-metabolic-regulation-of-cancer
#12
Kuldeep S Attri, Divya Murthy, Pankaj K Singh
Genetic mutations and metabolic reprogramming are two key hallmarks of cancer, required for proliferation, invasion, and metastasis of the disease. While genetic mutations, whether inherited or acquired, are critical for the initiation of tumor development, metabolic reprogramming is an effector mechanism imperative for adaptational transition during the progression of cancer. Recent findings in the literature emphasize the significance of molecular cross-talk between these two cellular processes in regulating signaling and differentiation of cancer cells...
March 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28198375/haploinsufficiency-networks-identify-targetable-patterns-of-allelic-deficiency-in-low-mutation-ovarian-cancer
#13
Joe Ryan Delaney, Chandni B Patel, Katelyn McCabe Willis, Mina Haghighiabyaneh, Joshua Axelrod, Isabelle Tancioni, Dan Lu, Jaidev Bapat, Shanique Young, Octavia Cadassou, Alena Bartakova, Parthiv Sheth, Carley Haft, Sandra Hui, Cheryl Saenz, David D Schlaepfer, Olivier Harismendy, Dwayne G Stupack
Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions...
February 15, 2017: Nature Communications
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
#14
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
#15
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/28192409/melanocyte-transformation-requires-complete-loss-of-all-pocket-protein-function-via-a-mechanism-that-mitigates-the-need-for-mapk-pathway-activation
#16
I D Tonks, P Mukhopadhyay, W A Schroder, A Sorolla, A W Mould, H Y Handoko, B Ferguson, H K Muller, P Keith, N K Hayward, G J Walker, G F Kay
Deregulation of p16INK4A is a critical event in melanoma susceptibility and progression. It is generally assumed that the major effect of loss of p16 function is mediated through the CDK-cyclin pathway via its influence on the pocket protein (PP) pRb. However, there are also two other PPs, p107 and p130, which, when phosphorylated by CDK-cyclin complexes, play a role in permitting cell progression. Cohorts of mice carrying melanocyte-specific knockouts (KOs) of various combinations of the three PPs were generated...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28192406/ras-erk-signaling-induces-phosphorylation-of-human-tle1-and-downregulates-its-repressor-function
#17
T Zahavi, A Maimon, T Kushnir, R Lange, E Berger, D Kornspan, R Grossman, S Anzi, E Shaulian, R Karni, H Nechushtan, Z Paroush
Signaling mediated by the Ras-extracellular signal-regulated kinase (Erk) pathway often leads to the phosphorylation of transcriptional regulators, thereby modulating their activity and causing concerted changes in gene expression. In Drosophila, the induction of multiple Ras-Erk pathway target genes depends on prior phosphorylation of the general co-repressor Groucho, a modification that downregulates its repressive function. Here, we show that TLE1, one of the four human Groucho orthologs, is similarly phosphorylated in response to Ras-Erk pathway activation, and that this modification attenuates its capacity to repress transcription...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28192402/loss-of-klf4-and-consequential-downregulation-of-smad7-exacerbate-oncogenic-tgf-%C3%AE-signaling-in-and-promote-progression-of-hepatocellular-carcinoma
#18
H Sun, Z Peng, H Tang, D Xie, Z Jia, L Zhong, S Zhao, Z Ma, Y Gao, L Zeng, R Luo, K Xie
Hyperactivation of transforming growth factor-β (TGF-β) signaling pathway is a common feature of hepatocellular carcinoma (HCC) progression. However, the driver factors leading to enhanced TGF-β activity are not well characterized. Here, we explore the mechanisms that loss of Krüppel-like factor 4 (KLF4) exacerbates oncogenic TGF-β signaling in human HCC. The expression of KLF4 and TGF-β signaling components in primary HCC and their clinicopathologic relevance and significance was evaluated by using tissue microarray and immunohistochemistry...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28192400/oncogenic-signaling-by-kit-tyrosine-kinase-occurs-selectively-on-the-golgi-apparatus-in-gastrointestinal-stromal-tumors
#19
Y Obata, K Horikawa, T Takahashi, Y Akieda, M Tsujimoto, J A Fletcher, H Esumi, T Nishida, R Abe
Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM)...
February 13, 2017: Oncogene
https://www.readbyqxmd.com/read/28192371/somatic-mutations-in-telomerase-promoter-counterbalance-germline-loss-of-function-mutations
#20
Lindley Maryoung, Yangbo Yue, Ashley Young, Chad A Newton, Cindy Barba, Nicolai S C van Oers, Richard C Wang, Christine Kim Garcia
Germline coding mutations in different telomere-related genes have been linked to autosomal-dominant familial pulmonary fibrosis. Individuals with these inherited mutations demonstrate incomplete penetrance of clinical phenotypes affecting the lung, blood, liver, skin, and other organs. Here, we describe the somatic acquisition of promoter mutations in telomerase reverse transcriptase (TERT) in blood leukocytes of approximately 5% of individuals with inherited loss-of-function coding mutations in TERT or poly(A)-specific ribonuclease (PARN), another gene linked to telomerase function...
February 13, 2017: Journal of Clinical Investigation
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