To decline cookies at any time, you may adjust your browser settings. DNA of frozen tissue and paired blood samples was isolated using a DNeasy blood and tissue mini kit and a QIAmp DNA blood midi kit (Qiagen), respectively, according to the manufacturer’s instruction. *, P < 0.05 compared with vehicle control (vehicle). Our findings have important implications for the management of patients with NKTCLs. Only SNVs in exons or in canonical splice sites were further analyzed. NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. 4A) and cell viability in a dose-dependent fashion (Fig. Lihat profil Choon kiat Gan di LinkedIn, komuniti profesional yang terbesar di dunia. Lim, Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc. Ang Choon Kiat has 4 jobs listed on their profile. To detect single-nucleotide variants (SNV), we used a discovery pipeline based on the Genome Analyzer Toolkit (GATK). Known somatic mutations in NKTCLs, such as TP53, KRAS, and NRAS (4), identified by exome sequencing were further validated by Sanger sequencing in the same tumors (Supplementary Table S2). Significance: Gene mutations causing NKTCL have not been fully identified. Importantly, NK-S1 cells treated with JAK3 siRNAs exhibited a significant reduction in cell proliferation and also decreased autophosphorylation of JAK3 and STAT5, compared with cells treated with control siRNAs (Fig. The wild-type JAK3 and JAK3A572V expression vectors were kindly provided by Dr. Brian Druker. Lim, Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S.L. There has been little progress in basic science and clinical research in this subtype of lymphoma, which continues to constitute a major challenge in managing these patients as there is currently no accepted standard first-line treatment for NKTCLs. MIGR1 expression vectors containing full-length wild-type JAK3 or JAK3A572V mutant were generously provided by Dr. Brian Druker (Howard Hughes Medical Institute, Chevy Chase, MD; ref. DNA was then extracted using a DNeasy blood and tissue mini kit (Qiagen). Experiments were repeated at least 3 times.y. See the complete profile on LinkedIn and discover Gan’s connections and jobs at similar companies. This is the first time that the Land Transport Authority (LTA) has introduced a festive-themed train. Lim, Development of methodology: G.C. Tan, S.L. Gan Xa. We conducted whole-exome sequencing and identified Janus kinase 3 ( JAK3 ) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. All variants retained following this step were considered to be novel. The next step uses a GATK Unified Genotyper that does the consensus calling to identify SNVs. Lee, I. Cutcutache, W. Yu, C.C.Y. Gan Arion. Gan Choon Kiat, deputy director of the LTA's corporate transformation office, was quoted by Channel NewsAsia as saying that more themed trains will be rolled out in future. 1). Teh, S.T. All results are expressed as mean ± SEM of 3 independent experiments. HRM difference curves deviating from the wild-type curve were considered to be harboring a mutation. Cells were seeded at 2 × 104 cells/100 μL/well in 96-well plates and treated with or without CP-690550 (Selleck Chemical, S5001) at various concentrations before being subjected to MTS assay (Promega). Despite multiagent chemotherapy and involved-field radiotherapy, the 5-year overall survival rate is approximately 9% for non-nasal NKTCLs and 42% for nasal NKTCLs (2, 3). Cells were harvested at indicated time intervals after IL-2 or CP-690550 treatment. 4B). Lim, Study supervision: S. Rozen, B.T. Conception and design: G.C. 4A and B). We use cookies to tailor your browsing experience. This article is highlighted in the In This Issue feature, p. 569. He is a practicing lawyer and is a Partner at Infinitus Law Corporation and Head of its Corporate, Commercial and Technology Department. Reciprocally, KHYG-1 cells transiently overexpressing a mutated JAK3 (JAK3A572V) cDNA showed IL-2–independent proliferation and autophosphorylation of JAK3 and STAT5 (Fig. B, cell viability was analyzed by MTS assay after the cells were treated with their respective treatment for 72 hours. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. 2C and D). Sino Group is one of the leading property developers in Hong Kong. Koo, S.Y. Earlier this month, SMRT announced that trains themed after the upcoming Star Wars VII: The Force Awakens movie will start operating from mid-December. Heng, A. Gan, S.T. ©2012 American Association for Cancer Research. As such, it is possible that the number of homozygous tumors reported is actually an underestimate and that this value should be regarded as a lower limit. Data were analyzed by paired t test, and values significantly different from control are shown as *, P< 0.05; **, P< 0.005; ***, P< 0.001. View the profiles of people named Choon Kiat Gan. IL-2–independent growth and constitutive JAK3 and STAT5 phosphorylation in a JAK3A572V-mutant NKTCL cell line. Koo, S.Y. The single EBER-negative case was a cutaneous deposit taken from a patient with EBER+ nasal NKTCLs (Supplementary Table S3). We are glad to play a part in our nation's 48th birthday celebration. Gan Teng. To determine the prevalence of JAK1 and JAK3 mutations in NKTCLs, we Sanger sequenced an additional 61 NKTCL formalin-fixed, paraffin-embedded (FFPE) cases. Captured DNA libraries were sequenced with the Illumina GAIIx Genome Analyzer, yielding 150 (2 × 75) base pairs from the final library fragments. The authors also thank the Lee Foundation for its support, Huang Dachuan and Waraporn Chan-on for proofreading the manuscript, and Sabrina Noyes for assistance in manuscript submission. Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). In summary, our studies identified, for the first time, frequent JAK3 mutations in NKTCLs. Experiments were repeated at least 3 times. However, this phenomenon was not observed in the K562 cells in which STAT5 phosphorylation is dependent on BCR/ABL1 (8) and not JAK3 (Fig. Sequencing PCR was carried out with ABI BigDye Terminator v3.1 (Life Technologies, catalog number 4337457) and cycled at 96°C for 1 minute; 29 cycles of 96°C for 10 seconds; 50°C for 5 seconds, and 60°C for 4 minutes. Choon Kiat Gan नाम के लोगों की प्रोफ़ाइल देखें. The cycling and melting conditions were as follows: 1 cycle of 98°C for 2 minutes; 39 cycles of 98°C for 5 minutes; 58°C for 10 minutes; 1 cycle of 95°C for 30 minutes; and a melt from 72°C to 95°C increasing at 0.2°C/s. All 3 missense mutations were predicted by PolyPhen to be damaging (5). Lim, Writing, review, and/or revision of the manuscript: G.C. Ong, K. Tay, R. Quek, K.-W. Yeoh, L.C. Gan has 3 jobs listed on their profile. Ong, P. Tan, B.T. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. These results were further confirmed by high-resolution melt (HRM) analysis (Supplementary Fig. We retained SNVs that passed additional quality filters (a quality by depth ≥5, a variant depth ≥5, a normal depth ≥5) and discarded any SNV close to a micro-indel or to several other SNVs. Thus, it is conceivable that the JAK3 mutation may play an important role in the pathogenesis of NKTCLs. Cancer Discovery Among the patients with JAK3 mutations, there were 17 heterozygous JAK3A572V, 2 homozygous JAK3A572V, 2 heterozygous JAK3A573V, 1 homozygous JAK3A573V, and 1 heterozygous with both JAK3A572V and JAK3A573V mutations. View Choon Chia's business profile as Infrastructure & Operation Director, Systems (Rail Asset O&M) at Land Transport Authority. Gan Choon Beng has been a GBN Mentor since 2008 and has worked with many mentees in various areas of business. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Mr Gan Juay Kiat was appointed Chief Executive Officer of SBS Transit Ltd on 1 March 2010. FFPE tissue blocks from 61 patients with NKTCLs were procured for mutation analysis. Choon Kiat Chen Solutions Director , China Mobile International Choon Kiat has more than 25 years in the Telco/ICT industry since attaining his degree in Computing Science(1994) and MBA(2000). The HRM curves were analyzed with the Bio-Rad Precision Melt Analysis Software. Land Transport Authority (LTA) Singapore is a entity based in 1 Hampshire Road, Singapore, 219428, Singapore, which employs 908 executives. Among these 4 members, JAK3 signaling is specifically related to T-cell development and proliferation (8) with loss-of-function mutations resulting in severe combined immunodeficiency characterized by the lack of T and NK cells (9). Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma, Management of T-cell and natural-killer-cell neoplasms in Asia: consensus statement from the Asian Oncology Summit 2009, Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years, International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes, P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan. Others With a Similar Name. Yuen Kin Pheng is Professional at Tasek Corp. Bhd. Copyright © 2021 by the American Association for Cancer Research. Apart from 4 older cases that cannot be interpreted, all but one case were positive for EBER, regardless of JAK3 mutation status. See the complete profile on LinkedIn and discover Ang Choon Kiat’s connections and jobs at similar companies. Tan, K. Tay, B.T. Ng, V. Rajasegaran, H.L. Matched fresh-frozen tissue and peripheral blood samples were obtained from 4 consented patients with NKTCLs for whole-exome sequencing. In line with the functional importance of the activating JAK3 mutations identified, we tested whether JAK3 mutations could confer IL-2–independent growth to the NKTCL cell line (NK-S1) that harbors a homozygous JAK3A572V mutation. Lim, Supplied pathologic diagnosis for case series: L. Tan. 8). Commuters can also grab the Christmas tree-shaped cards hanging from the handrails to use as greeting cards. Consistent with the high frequency of JAK3 mutations (35%) in NKTCLs, use of CP-690550 in the JAK3-mutant NKTCL cell line showed inhibition in the phosphorylation of STAT5 along with reduced cell viability. To further confirm the involvement of JAK/STAT signaling in the survival of NKTCLs, we next evaluated the effect of a pan-JAK inhibitor, CP-690550, in NK-S1, KHYG-1, and K562 cells. B, NK-S1 cell lysates were harvested for Western blotting, and the results showed that phosphorylation of JAK3 and STAT5 are IL-2–independent. Teh, S.T. Gan Chimeg. In total, we found mutations in JAK3 in 23 of 65 (35.4%) cases (Supplementary Table S3) and for JAK1, besides the case with concomitant JAK1Y652D and JAK3A572V mutations described above, no additional mutations were identified. The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. The diagnosis of NKTCL was made according to the 2008 World Health Organization classification of tumors of the hematopoietic and lymphoid tissues (24). Natural killer (NK) cells as a responder to interleukin 2 (IL 2). All samples were centrally reviewed by our hematopathologists. However, compared with the more common B-cell lymphomas, very little is known about its molecular characteristics and pathogenesis. Gan. Natural killer/T-cell lymphoma (NKTCL) is particularly prevalent in Asian countries and some parts of Latin America. The JAK3, JAK1, JAK2, and TYK2 mutation status in these samples was confirmed by Sanger sequencing of all coding exons. View Ang Choon Kiat Amos’ profile on LinkedIn, the world’s largest professional community. It accounts for up to half of all mature TCL cases in Asia (1). Whole-exome sequencing was successfully conducted on fresh-frozen NKTCLs and paired blood samples from 4 different patients. Artnexus Design is the appointed creative agency for the NDP 2013 publicity production. Ng, S.T. D, phosphorylation of JAK3 and STAT5 in KHYG-1 cells were IL-2–dependent. Presently, Khai Choon Gan occupies the position of Non-Independent Non-Executive Chairman for HL Global Enterprises Ltd., Non-Executive Chairman of Beijing Fortune Hotel Co., Ltd. and Managing Director at Hong Leong International (Hong Kong) Ltd. We use cookies to tailor your browsing experience. Join Facebook to connect with Kiat Gan and others you may know. A, NK-S1, KHYG-1, and K562 cells were treated with CP-690550 for 48 hours, and the effect on STAT5 phosphorylation was evaluated by Western blotting. C, KHYG-1 cells carrying wild-type JAK3 showed IL-2–dependent proliferation. These results indicate that the JAK3-activating mutations are gain-of-function alleles and contribute to the constitutive activity of the JAK/STAT pathway in an IL-2–independent manner. One tumor harbored both JAK1Y652D and JAK3A572V mutations, whereas the other tumor harbored a JAK3A573V mutation. Lim, Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G.C. A, NK-S1 cells were treated with 100 nmol/L JAK3 siRNA (si-JAK3) or control siRNA (si-Ctrl) for 24 hours before being subjected to proliferation assays up to 72 hours (right). Choon Kiat Gan. Koo, S.Y. The JAK/STAT pathway is a key component in normal hematopoiesis. Koo, K.-W. Yeoh, C.C.Y. Ong, K.-W. Yeoh, K.A. JAK3A572V mutation causes constitutive JAK3 activity and IL-2–independent proliferation of NKTCL cells. and was admitted to the Singapore Bar in 1978. Teh, S.T. View Yuen Kin Pheng’s professional profile on Relationship Science, the database of decision makers. eISSN: 2159-8290 This study was approved by the SingHealth Centralized Institutional Review Board (CIRB), study number 2004/407/B. The train, which will run till Dec 27, was launched at Ang Mo Kio station by Transport Minister Khaw Boon Wan, who rode it to Marina Bay station with nine students from Pathlight School. SBS Transit chief executive Gan Juay Kiat has resigned due to an incident of “personal indiscretion”, according to a report by The Straits Times on Friday (28 December). Facebook gives people the power to share and makes the world more open and connected. Ong, S. Rozen, P. Tan, B.T. Domain structure of JAK3 (bottom) and the positions of JAK3A572V(c.1715C>T) and JAK3A573V (c.1718C>T; top) identified through Sanger sequencing of NKTCL samples. K562 (CCL-234) was purchased from American Type Culture Collection and cultured in DMEM supplemented with 10% heat-inactivated FBS and 10% equine serum. B, KHYG-1 cells were transiently transfected with wild-type JAK3 (JAK3 WT) or mutated JAK3 expression vectors (i.e., JAK3A572V). NK-S1, established from a previously described NKTCL xenograft (27), was cultured in Dulbecco’s Modified Eagle’s Medium (DMEM; Life Technologies) supplemented with 10% heat-inactivated FBS and 10% equine serum. Cellular studies revealed that the NK-S1 cells harboring the homozygous JAK3A572V mutation are able to proliferate in cell culture without IL-2 stimulation, with constitutive expression of both phosphorylated JAK3 and STAT5. This latter difference was not statistically significant (Supplementary Table S3). In line with these observations, we identified the presence of activating JAK3 mutations in 35% of NKTCL tumors. For Sanger sequencing, PCR was carried out with Platinum Taq Polymerase (Life Technologies, catalog number 10966-083) and cycled at 95°C for 10 minutes; 39 cycles of 95°C for 30 seconds; 60°C for 30 seconds, 72°C for 1 minute, and a final extension of 72°C for 10 minutes. 4C). Both NK-S1 and KHYG-1 cells showed a dose-dependent reduction in STAT5 phosphorylation. The extent of drug-induced apoptosis was evaluated by Annexin V-FITC (BD Biosciences) staining. 3B). Between 8pm and 10pm from Dec 21-24, artists from the Band of Doodlers, the art collective behind the decorations, will be drawing portraits for commuters on the cards for free. Sanger sequencing and HRM (25, 26) were used to confirm the JAK3 and JAK1 mutations identified and validate their prevalence in our NKTCL patient population. View Gan Chin Kiat’s profile on LinkedIn, the world’s largest professional community. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. In parallel, 50% of extra-nasal cases possessed JAK3 mutations and 31.7% of nasal cases had JAK3 mutations. CP-690550, a novel pan-JAK inhibitor, has recently been shown to inhibit adult TCL/leukemia (ATLL) cells (22) and ATLL xenograft tumors and is currently in phase III trials for the treatment of rheumatoid arthritis (23). The coding exons of JAK3 were fully sequenced in these 3 cell lines, and we confirmed that only NK-S1 harbored a homozygous JAK3A572V mutation. Cancer Discov; 2(7); 591–7. These are some of the notable cases which SPD officers handled in 2011: In PP v Abdul Razak Bin Hamid and PP v Tan Chye Guan Martin, the accused persons were both heinous child molesters, dubbed the “Letterbox Molester” and “Heartbeat Molester” respectively.They engaged in ruses to con children into physical contact and committed the offences over 20 years and 11 years respectively. Recent data suggest that mutations resulting in persistent activation of JAK/STAT signaling are involved in the pathogenesis of T-cell acute lymphoblastic lymphoma/leukemia, cutaneous TCL, mantle cell lymphoma, acute megakaryoblastic leukemia, and myeloproliferative diseases (8, 10–16). To decline cookies at any time, you may adjust your browser settings. Koo, S.Y. S1). In contrast, JAK3 wild-type KHYG-1 cells were clearly IL-2–dependent (Fig. He currently oversees The GBN Mentoring Program together with Seow Kiat Wang.. The primer sequences used for validation are listed in Supplementary Table S4. Thank you for sharing this Cancer Discovery article. By continuing to use Gov.sg, you accept our use of cookies. See more people named Choonkiat Gan. Zhi Jiang Zang, Choon Kiat Ong, Ioana Cutcutache, Willie Yu, Shen Li Zhang, Dachuan Huang, Lian Dee Ler, Karl Dykema, Anna Gan, Jiong Tao, Siyu Lim, Yujing Liu, P. Andrew Futreal, Heike Grabsch, Kyle Furge, Liang Kee Goh, Steve Rozen, Bin Tean Teh, Patrick Tan Cancer Research, 1 January 2011 doi: 10.1158/0008-5472.CAN-10-1749 There is thus an urgent need to identify novel genetic aberrations and potential treatment targets in NKTCLs. Besides hematologic neoplasia, nonhematologic cancers, including breast, stomach, and lung cancer, have also been found to harbor JAK3 mutations (17, 18). Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. JAK-mutant (NK-S1) cells showed IL-2–independent growth (Fig. Jak-STAT pathway is involved in the induction of TNF-beta gene during stimulation by IL-2, Activating alleles of JAK3 in acute megakaryoblastic leukemia, Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency, Somatically acquired JAK1 mutations in adult acute lympho-blastic leukemia, Mutations of JAK2 in acute lymphoblastic leukaemias associated with Down’s syndrome, FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma, Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma, Activation status of the JAK/STAT3 pathway in mantle cell lymphoma, JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults, A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera, Somatic mutations of JAK1 and JAK3 in acute leukemias and solid cancers, Somatic mutations affect key pathways in lung adenocarcinoma, Activating mutations in human acute megakaryoblastic leukemia, Array-based genomic resequencing of human leukemia, Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models, The JAK kinase inhibitor CP-690,550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation, CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP, The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications, KRAS mutation detection in paired frozen and formalin-fixed paraffin-embedded (FFPE) colorectal cancer tissues, An Epstein-Barr virus positive natural killer lymphoma xenograft derived for drug testing, A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation, Lung Microbiome and Lung Cancer Prognosis, Pan-Cancer Analysis of HLA LOH as a Method of Immune Evasion, Cancer Epidemiology, Biomarkers & Prevention, Disclosure of Potential Conflicts of Interest. Mr Gan Khai Choon (iii) Mr Hoh Weng Ming (iv) Mr Tan Aik-Leang (v) Mr Neo Poh Kiat (vi) Mr Yan Ping (vii) Mr Han Yi Yong (viii) Mr Raymond … Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt … Lee, L.C. 3A). Lim, C. Goh, W. Yu, C.C.Y. Gan Teng (Reno) Gan Teng. ISSN: 2159-8274, Sign In to Email Alerts with your Email Address. Allen, W.S. Tan, L. Tan, S.C. Chong, K. Tay, M. Tao, R. Quek, S. Loong, K.-W. Yeoh, S.P. JAK3 siRNA or control siRNA (Dharmacon) were transfected into NK-S1 cell line using RNAiMAX (Invitrogen) according to the manufacturer’s protocols. This study was funded by the National Medical Research Council of Singapore (NMRC/PPG/NCC/2011) as well as a grant from HSBC Trustee (Singapore) Limited as trustees of the Major John Long Trust Fund and the Chew Woon Poh Trust Fund. These data are compelling and suggest a potential target for this otherwise fatal disease. Ng, V. Rajasegaran, H.L. The presence of nonmalignant stroma (our samples contained at least 50% tumor content) or tumor subclones makes it difficult to assess whether these “heterozygous” tumors might actually represent a mixture of JAK3 homozygous–mutated cancer cells admixed with normal tissue. Effects of CP-690550 on NKTCL cell lines. "Every month or so we will be working with our public transport operators to have more themed trains in the next year," he said. Primer sequences used for validation are listed in Supplementary Table S4 के लोगों की प्रोफ़ाइल देखें Cutcutache W.. American Association for cancer Research presence of activating JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation to! Cp-690550 treatment Sign in to Email Alerts with your Email address, work history, and TYK2 mutation status these... Gan नाम के लोगों की प्रोफ़ाइल देखें data are compelling and suggest a potential target for this otherwise fatal.! 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