Prof Soon Thye LIMDr Nicholas GRIGOROPOULOS Dr Dachuan HUANGDr Jing TANDr Jing Quan LIMDr Miriam TAODr Tiffany TANGDr Jason CHANDr Nagavalli d/o SOMASUNDARAMDr Mohamed Farid BIN HARUNAL RASHIDDr Nagarajan CHANDRAMOULIDr Chee Leong CHENGJeslin HAJane PANGEsther WONGBurton CHIADaryl CHEAH Sabrina HISSHAMYurike LAURENSIAKelila CHAIAlisa SAIRIHaniffa HASANLay Poh KHOOTony TAN
The Lymphoma Genomic Translational Laboratory, led by Principal Investigator Dr Choon Kiat ONG, is dedicated to gaining a better understanding of the pathogenesis and aetiology of lymphoma and subsequently translating significant findings into novel treatment approaches for patients through clinical trials. Lymphoma is a very complex disease with many different subtypes. Our research focuses mainly on non-Hodgkin’s lymphoma, especially T and NK cell lymphomas which are more prevalent in Asia. Besides understanding the disease through the use of various types of sequencing methodologies, we have also developed patient derived xenograft (PDX) models which are highly relevant to clinical drug testing and development. This capability allows us to further verify our discoveries at the genomic level, generating preclinical data and bringing the studies towards clinical trials. We are also in a good position to partner with pharmaceutical and diagnostic companies to develop drugs and biomarkers, respectively.
Our contribution to the understanding of the disease is summarized in Figure 1. Using genomic approaches, we have discovered novel therapeutic targets in Natural Killer/T-cell lymphoma (NKTCL) 1,2,3 and Monomorphic Epitheliotropic Intestinal T-cell lymphoma4, which allow us to develop novel drugs against the disease5. Recently, we have also discovered novel biomarkers of response to immune checkpoint inhibitors in NKTCL which will allow us to better select patients for this class of drugs6. In partnership with Lucence Diagnostics, we have successfully developed a clinical grade assay for the detection of these biomarkers in our patients, moving our discovery from “Bench to Bedside”. We have contributed to improve accuracy of prognosis and diagnosis of T and NK-cell lymphoma with the eventual aim of improving treatment7,8,9,10. Using a germline approach, we have successfully gained further insights into the pathobiology of these aggressive diseases 11-13. We will continue to study and understand this group of diseases, devising novel therapeutic strategies to improve their clinical outcome.
Over the years, our laboratory has secured research grants from various funding agencies, namely the National Medical Research Council (NMRC), the National Health Innovation Centre (NHIC), and the NCC Research Fund (NCCRF). In 2019, our team was awarded with a $10Mil Large Collaborative Grant (LCG) by NMRC, for a cross-institutional project entitled “SYMPHONY”. “SYMPHONY” is an extension of the existing Translational and Clinical Research (TCR) programme (2014 – 2019), and it builds upon the findings and collaborations over the last 5 years to further the understanding of and develop novel strategies to combat this debilitating disease. We have also received industrial support for several projects from pharmaceutical companies, including Bayer Pharmaceuticals, ASLAN, Principia Biopharma, and SYNthesis Pte Ltd, and we are actively seeking out more potential partners for collaborations.
Dr ONG, along with other collaborating scientists in the field of cancer research, was awarded the “AACR Team Science Award 2018” by the American Association for Cancer Research (AACR), recognising the outstanding interdisciplinary team’s work in furthering the knowledge of Asian prevalent cancers and contributing to the progress of cancer detection, treatment and prevention. Dr Ong is currently leading the whole-genome sequencing of T and natural killer-cell lymphoma at the International Cancer Genomic Consortium (ICGC). This initiative has proudly placed Singapore on the world map in the field of cancer genomic research.
Figure 1. Our contributions to the understanding of NKTCL and PTCL. We discovered frequent mutation of JAK3 in NKTCL and have developed and tested JAK3 specific molecules with Principia Biopharma. We have recently shown that relapsed and refractory NKTCL patients response well to immune checkpoint inhibitor, pembrolizumab and discovered that PD-L1 structural rearrangement (SR) is highly prevalent in durable responders, but not in the non-responders. Together with Lucence Diagnostic, we co-developed a clinical grade assay which is ready for clinical deployment. Besides upregulating PD-L1 through the PD-L1 SR, we have shown that STAT3 activating mutation, which is highly prevalent in NKTCL, could directly bind to the PD-L1 promoter to upregulate the protein. Besides JAK/STAT pathway, we have observed epigenetic alterations highly prevalent in PTCL. We have discovered the importance of JAK-STAT and MEK-ERK pathways in MEITL, an aggressive and fatal PTCL. We recently demonstrated that combinatorial therapy works very well in this lymphoma and hope to improve the clinical course of this disease. Using genome-wide association study (GWAS) and sequencing, we have identified variants in HLA-DPB1, HLA-DRB1, IL18RAP and FAM160A as susceptible SNPs that predispose individual to NKTCL. Together with NCI, we have also discovered and developed diagnostic biomarker for subtypes of PTCL.
1. Tan KM, Chia B, Lim JQ, Khoo LP, Cheng CL, Tan L, Poon E, Somasundaram N, Farid M, Tang TPL, Tao M, Cheah DMZ, Laurensia Y, Pang JWL, Song T, Tan J, Huang D, Kim SJ, Kim WS, Ong CK*, Lim ST*, Chan JY*. A clinicohaematological prognostic model for nasal-type natural killer/T-cell lymphoma: A multicenter study. Sci Rep. 2019 Oct 18;9(1):14961. (*Co-Corresponding author). Impact Factor: 4.011.
2. Peng RJ, Han BW, Cai QQ, Zuo XY, Xia T, Chen JR, Feng LN, Lim JQ, Chen SW, Zeng MS, Guo YM, Li B, Xia XJ, Xia Y, Laurensia Y, Chia BKH, Huang HQ, Young KH, Lim ST, Ong CK*, Zeng YX*, Bei JX*. Genomic and Transcriptomic Landscapes of Epstein-Barr Virus in Extranodal natural killer T-cell lymphoma. Leukemia 2019 Jun;33(6):1451-1462. (Co-Corresponding author). Impact Factor: 11.702.
3. Chan JY, Ng AYJ, Cheng CL, Nairismägi ML, Venkatesh B, Cheah DMZ, Li ST, Chan SH, Ngeow J, Laurensia Y, Lim JQ, Pang JWL, Nagarajan S, Song T, Chia B, Tan J, Huang D, Goh YT, Poon E, Somasundaram N, Tao M, Quek RHH, Farid M, Khor CC, Bei JX, Tan SY, Lim ST, Ong CK*, Tang T*. Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma. Blood Cancer J. 2018 Nov 12;8(11):111. (*Co-Corresponding author). Impact factor: 8.125.
4. Song TLL, Nairismägi ML, Laurensia Y, Lim JQ, Tan J, Li ZM, Pang WL, Kizhakeyil A, Wijaya GC, Huang D, Nagarajan S, Chia BKH, Cheah D, Liu YH, Zhang F, Rao H, Tang T, Wong EKY, Bei J, Iqbal J, Grigoropoulos NF, Ng SB, Chng WJ, Teh BT, Tan SY, Verma NK, Fan H, Lim ST, Ong CK. Oncogenic Activation of STAT3 Pathway Drives PD-L1 Expression in Natural Killer/T cell Lymphoma. Blood. 2018 Sep 13;132(11):1146-1158. (Corresponding author). Impact factor: 15.132.
5. Nairismägi ML, Gerritsen ME, Li ZM, Wijaya GC, Chia BKH, Laurensia Y, Lim JQ, Yeoh KW, Yao XS, Pang WL, Bisconte A, Hill RJ, Bradshaw JM, Huang D, Song TLL, Ng CCY, Rajasegaran V, Tang T, Tang QQ, Xia XJ, Kang TB, Teh BT, Lim ST, Ong CK*, Tan J*. Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia. 2018 May;32(5):1147-1156. (*Co-Corresponding author). Impact Factor: 11.702.
6. Li Z, Xia Y, Feng LN, Chen JR, Li HM, Cui J, Cai QQ, Sim KS, Nairismägi ML, Laurensia Y, Meah WY, Liu WS, Guo YM, Chen LZ, Feng QS, Pang CP, Chen LJ, Chew SH, Ebstein RP, Foo JN, Liu J, Ha J, Khoo LP, Chin ST, Zeng YX, Aung T, Chowbay B, Diong CP, Zhang F, Liu YH, Tang T, Tao M, Quek R, Mohamad F, Tan SY, Teh BT, Ng SB, Chng WJ, Ong CK, Okada Y, Raychaudhuri S, Lim ST, Tan W, Peng RJ, Khor CC, Bei JX. Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. Lancet Oncology. 2016 Sep;17(9):1240-7. Impact factor: 24.725.
7. Nairismägi ML, Tan J, Lim JQ, Nagarajan S, Ng CC, Rajasegaran V, Huang D, Lim WK, Laurensia Y, Wijaya GC, Li ZM, Cutcutache I, Pang WL, Thangaraju S, Ha J, Khoo LP, Chin ST, Dey S, Poore G, Tan LH, Koh HK, Sabai K, Rao HL, Chuah KL, Ho YH, Ng SB, Chuang SS, Zhang F, Liu YH, Pongpruttipan T, Ko YH, Cheah PL, Karim N, Chng WJ, Tang T, Tao M, Tay K, Farid M, Quek R, Rozen SG, Tan P, Teh BT, Lim ST, Tan SY, Ong CK. JAK-STAT and G protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. Leukemia. 2016 Jun;30(6):1311-9. (Corresponding author). Impact factor: 12.104.
1. 1. Koo GC, Tan SY, Tang T, et al: Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma. Cancer Discovery 2:591-597, 2012
2. Song TL, Nairismagi ML, Laurensia Y, et al: Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma. Blood 132:1146-1158, 2018
3. Peng R-J, Han B-W, Cai Q-Q, et al: Genomic and transcriptomic landscapes of Epstein-Barr virus in extranodal natural killer T-cell lymphoma. Leukemia 33:1451-1462, 2019
4. Nairismagi ML, Tan J, Lim JQ, et al: JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma. Leukemia 30:1311-9, 2016
5. Nairismagi M, Gerritsen ME, Li ZM, et al: Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma. Leukemia 32:1147-1156, 2018
6. Lim J-Q, Tang T, Cai Q-q, et al: Recurrent PD-L1 Structural Rearrangements in Natural Killer/T Cell Lymphoma Patients with Complete Response to PD-1 Blockade Therapy. bioRxiv:372383, 2018
7. Ng SB, Chung TH, Kato S, et al: Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes. Haematologica 103:278-287, 2018
8. Heavican TB, Bouska A, Yu J, et al: Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma. Blood 133:1664-1676, 2019
9. Tan KM, Chia B, Lim JQ, et al: A clinicohaematological prognostic model for nasal-type natural killer/T-cell lymphoma: A multicenter study. Scientific Reports 9:14961, 2019
10. Amador C, Greiner TC, Heavican TB, et al: Reproducing the Molecular Subclassification of Peripheral T-cell Lymphoma-NOS by Immunohistochemistry. Blood, 2019
11. Li Z, Xia Y, Feng LN, et al: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. Lancet Oncol 17:1240-7, 2016
12. Chan JY, Ng AYJ, Cheng CL, et al: Whole exome sequencing identifies recessive germline mutations in FAM160A1 in familial NK/T cell lymphoma. Blood cancer journal 8:111-111, 2018
13. Guo-Wang Lin, C Xu, K Chen, H-Q Huang, et al: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations. Lancet Oncology, 2019 (in-press)
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