Prof Soon Thye LIMDr Dachuan HUANGDr Jing Quan LIMDr Nicholas GRIGOROPOULOSDr Shin Yeu OngDr Miriam TAODr Jason CHANDr Nagavalli d/o SOMASUNDARAMDr Mohamed Farid BIN HARUNAL RASHIDDr Nagarajan CHANDRAMOULIDr Chee Leong CHENGNur Izzah Nabilah bte HUSSEIN
Ayuni BINTE MUHAMMAD TAIB
Beng Hooi PHANG
Herty LIANYKelila CHAI
Lay Poh KHOO
LIM Xiang Yun
The Lymphoma Genomic Translational Research 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), humanized and transgenic mouse 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, which allow us to develop therapeutic strategies against the disease3-7. To understand the pathogenic contribution of Epstein-Barr virus (EBV), we have also sequenced the virus genome from these tumors. We observed transcriptional defects at the BARTs miRNA and the disruption of host NHEJ by EBV integration, implying novel pathogenesis mechanisms of EBV5. Recently, we have demonstrated that a sub-group of relapsed/refractory NKTCL patients responded very well to immune checkpoint (ICP) inhibitors6,7. Through analysis of genomic, histological and clinical data, we have discovered novel biomarkers of response in NKTCL which will allow us to better select patients for ICP blockade therapy8. 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”9,10. Using a germline approach, we have successfully gained further insights into the pathobiology of these aggressive diseases11-14. More recently, we have also developed a 7-SNP-based classifier that could predict patients’ outcome and can be used as a supplement to current risk indicators, aiding clinical decision making19. Besides SNPs, we have also shown that peripheral blood neutrophil-lymphocyte ratio (NLR) could also be a potential prognostic marker18.
Using similar research strategies, we have deciphered the genomic landscape of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)15,16, which allow us to design rational therapeutic strategies with the help of quadratic phenotypic optimization platform (QPOP). The use of QPOP also enable us to identified effective combinatorial drug treatment for a hepatosplenic T-cell lymphoma (HSTL) patient17. Our team has improved the accuracy of prognosis and diagnosis of T and NK-cell lymphoma with the eventual aim of improving treatment20-25. We will continue to study and understand this group of diseases, devising novel therapeutic strategies to improve their clinical outcome. In addition, we are developing better analysis algorithm to improve our genomic analysis pipeline26.
Over the years, our laboratory has secured research grants from various funding agencies, namely the National Medical Research Council (NMRC) and the NCC Research Fund (NCCRF). In 2019, our team was awarded with the 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 and SymBio Pharmaceuticals Limited, 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.
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 and discovered that PD-L1 structural rearrangement (SR) is highly prevalent in durable responders, but not in the non-responders. Together with Lucence Diagnostic, a clinical grade assay was developed and 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.
1Koo 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.
2Song 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.
3Nairismagi 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.
4Huang D, Song TL, Nairismägi ML, et al: Evaluation of the PIK3 pathway in peripheral T-cell lymphoma and NK/T-cell lymphoma. Br J Haematol. 189(4):731-744, 2020.
5Peng 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.
6Kwong YL, Chan TSY, Tan D, et al: PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood. 129(17):2437-2442, 2017.
7Kim SJ, Lim JQ, Laurensia Y, et al: Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study. Blood. 2020 Aug 7.
8Lim JQ, Huang D, Tang T, et al: Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma.. Leukemia. 2020
9Ngeow KC, Choudhury Y, Tan D, et al: Ultrasensitive multiplex detection of structural rearrangements in ALK, RET, ROS1 and PD-L1 using a comprehensive next-generation sequencing assay. ASCO 2020 poster abstract 3572.
10Poh J, Ngeow KC, Pek M, et al. Analytical and clinical validation of an amplicon-based next generation sequencing assay for ultrasensitive detection of circulating tumor DNA. PLoS One 17(4):e0267389. 2022.
11Li 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.
12Lin GW, Xu C, Chen K, et al: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations. Lancet Oncology 21(2):306-316, 2020.
13Chan 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.
14Ong SY, Lim JQ, Grigoropoulos N, et al: No association between ECSIT germline mutations and hemophagocytic lymphohistiocytosis in natural killer/T-cell lymphoma. Haematologica. 2021 Oct 13.
15Nairismagi 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.
16Huang D, Lim JQ, Cheah DMZ, et al: Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma. Blood Adv. 4(19):4769-4774, 2020.
17de Mel S, Rashid MBM, Zhang XY, et al: Application of an ex-vivo drug sensitivity platform towards achieving complete remission in a refractory T-cell lymphoma. Blood Cancer J. 10(1):9. 2020.
18Tan 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.
19Tian XP, Ma SY, Young KH, et al. A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma [published online ahead of print, 2021 Mar 16]. Blood. 2021; blood.2020010637.
20Ng 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.
21Heavican 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.
22Amador C, Greiner TC, Heavican TB, et al: Reproducing the Molecular Subclassification of Peripheral T-cell Lymphoma-NOS by Immunohistochemistry. Blood, 2019.
23Lone W, Bouska A, Sharma S, et al: Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma. Clin Cancer Res. 27(21):6039-6053. 2021.
24Oon ML, Lim JQ, Lee B, et al: T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes. Cancers (Basel) 13(2):340, 2021
25Wai CMM, Chen S, Phyu T, et al: Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS. Haematologica, 2022.
26Lim JQ, Lim ST, Ong CK: Misaligned sequencing reads from the GNAQ-pseudogene locus may yield GNAQ artefact variants. Nature Communications 13:458, 2022.
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