Prof Soon Thye LIM Dr Dachuan HUANG Dr Jing Quan LIM Dr Nicholas GRIGOROPOULOS Dr Shin Yeu Ong Dr Miriam TAO Dr Jason CHAN Dr Nagavalli d/o SOMASUNDARAM Dr Mohamed Farid BIN HARUNAL RASHID Dr Nagarajan CHANDRAMOULI Dr Chee Leong CHENG Ayuni BINTE MUHAMMAD TAIB Beng Hooi PHANG Kelila CHAI Kerry Lim Alisa SAIRI Haniffa HASAN Jeslin HA Lay Poh KHOO Nur Fazlin MOHAMED NOOR Fathimah RAFI’EE LIM Xiang Yun
The Lymphoma Genomic Translational Research Laboratory, led by Principal Investigator Associate Professor 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 natural killer/T-cell lymphoma (NKTL) and peripheral T-cell lymphoma (PTCL) is summarized in Figure 1.
We discovered frequent alteration of the JAK/STAT pathway in natural killer/T-cell lymphoma (NKTL)1,2 and demonstrated efficacy of inhibiting JAK33 and STAT34 in this aggressive disease. Through a collaborative study with Bayer, we have demonstrated that PI3K might be a potential therapeutic target for NKTL5. Recently, we have described the aberrant Super-enhancer (SE) landscape and transcriptional program in NKTL and identified transcription factor, TOX2 and its key downstream effector, PRL-3 as potential therapeutic targets6. We have also discovered aberrant JAK/STAT signalling conferred resistance to histone deacetylase (HDAC) inhibitor, chidamide in NKTL and demonstrated clinical efficacy in combine use of chidamide and ruxolitinib (JAK2 inhibitor)7. We have demonstrated that a sub-group of relapsed/refractory (RR) NKTL patients responded very well to immune checkpoint (ICP) inhibitors8. Through analysis of genomic, histological and clinical data, we have discovered PD-L1 3’UTR structural rearrangement (SR) as a biomarker of response to PD-1 blockade therapy in NKTL which allowed us to better select patients for ICP blockade therapy9. 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 Bedside10.
To understand other pathogenic factors contributing to NKTL, we have sequenced the Epstein-Barr virus (EBV) genome from these tumors. We observed transcriptional defects at the BARTs miRNA and the disruption of host NHEJ1 by EBV integration, implying novel pathogenesis mechanisms of EBV11. Using genome-wide association study (GWAS) and sequencing approaches, we have identified variants in HLA-DPB1, HLA-DRB1, IL18RAP and FAM160A as susceptible single nucleotide variants (SNPs) that predispose individual to NKTL.12-15
In collaboration with various international cancer centers, genomic profiling of NKTL samples with well curated clinical information enable us to develop a genomic prognostic model (GPM), consisting of 13 somatically mutated genes which can significantly improve the current prognostic model International Prognostic Index (IPI), PI for Natural-Killer cell lymphoma (PINK) and PINK-Epstein-Barr virus (PINK-E).16 Importantly, the GPM can predict the outcome of patient with early-stage localized disease post radio-chemotherapy, allowing us to monitor and stratify these patients for more aggressive treatment. Similarly, using germline information, 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 making.17 We have also identified other prognostic factors such as the peripheral blood neutrophil-lymphocyte ratio (NLR)18 and methylation mark on circulating tumor DNA19 significantly associated with the survival outcome of NKTL patients. The integration of these prognostic factors will be further investigated.
Using similar research strategies, we have deciphered the genomic landscape of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)20,21, which allow us to design rational therapeutic strategies with the help of quadratic phenotypic optimization platform (QPOP). The QPOP is an AI-driven ex vivo drug combination platform which enable efficient identification of effective drug combination and we have identified an optimal combination of romidepsin (HDAC inhibitor) and pimozide (STAT5 inhibitor) for the treatment of MEITL.21 This platform was first tested successfully in a patient with RR hepatosplenic T-cell lymphoma who achieved complete remission for more than a year, despite failing high dose chemotherapy and autologous transplant.22 We have recently applied this platform to 71 patients with RR non-Hodgkin’s lymphoma, demonstrating a promising response rate of 50%.23
To improve diagnosis of the highly complex T and NK-cell lymphoma with the eventual aim of improving treatment, our team has been working with the lymphoma group at University of Nebraska and other collaborators to identify potential diagnostic biomarkers for subtyping of PTCL.24-31 Finally, as a genomic lab, we are constantly improving our analysis pipeline and continue to build up our bioinformatic capability.32
Over the years, our laboratory has secured research grants from various funding agencies, namely the National Medical Research Council (NMRC), the NCC Research Fund (NCCRF) and the Khoo Foundation. 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 lymphoma and develop novel strategies to combat this debilitating disease. We have also received industrial support for several projects from international pharmaceutical companies, including ScinnoHub and SymBio Pharmaceuticals Limited, as well as local biotech companies such as KYAN Technologies and Lucence Health. We are actively seeking out more potential partners for collaborations, and will continue to channel resources into bringing the programme to greater heights while maintaining our avenue as a centre for excellence in therapeutic targeting of lymphoma to ensure that research into mechanisms of lymphoma can be effectively translated into the healthcare settings in a cost-effective manner.
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.
Selected publications:
References:
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. 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
4. Wang Y, Zhou W, Chen J, et al: Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma. MedComm (2020) 4:e284, 2023
5. Huang 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 189:731-744, 2020
6. Zhou J, Toh SH, Tan TK, et al: Super-enhancer-driven TOX2 mediates oncogenesis in Natural Killer/T Cell Lymphoma. Mol Cancer 22:69, 2023
7. Chen J, Zuo Z, Gao Y, et al: Aberrant JAK-STAT signaling-mediated chromatin remodeling impairs the sensitivity of NK/T-cell lymphoma to chidamide. Clin Epigenetics 15:19, 2023
8. Kim 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
9. Lim JQ, Huang D, Tang T, et al: Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia, 2020
10. Poh 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:e0267389, 2022
11. 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
12. 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
13. Lin 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 Oncol 21:306-316, 2020
14. 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
15. Ong SY, Lim JQ, Grigoropoulos N, et al: No association between ECSIT germline mutations and hemophagocytic lymphohistiocytosis in natural killer/T-cell lymphoma. Haematologica 106:1737-1739, 2021
16. Lim JQ, Huang D, Chan JY, et al: A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort. Am J Hematol, 2022
17. Tian XP, Ma SY, Young KH, et al: A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma. Blood 138:452-463, 2021
18. 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
19. Tian XP, Zhang YC, Lin NJ, et al: Diagnostic performance and prognostic value of circulating tumor DNA methylation marker in extranodal natural killer/T cell lymphoma. Cell Rep Med 4:100859, 2023
20. 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
21. Huang D, Lim JQ, Cheah DMZ, et al: Whole-genome sequencing reveals potent therapeutic strategy for monomorphic epitheliotropic intestinal T-cell lymphoma. Blood Adv 4:4769-4774, 2020
22. de 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 Journal 10:9, 2020
23. Goh J, De Mel S, Hoppe MM, et al: An ex vivo platform to guide drug combination treatment in relapsed/refractory lymphoma. Sci Transl Med 14:eabn7824, 2022
24. 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
25. Herek TA, Bouska A, Lone W, et al: DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS. Blood 140:1278-1290, 2022
26. Amador C, Bouska A, Wright G, et al: Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice. J Clin Oncol 40:4261-4275, 2022
27. Lone W, Bouska A, Sharma S, et al: Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma. Clin Cancer Res 27:6039-6053, 2021
28. 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
29. Amador C, Greiner TC, Heavican TB, et al: Reproducing the molecular subclassification of peripheral T-cell lymphoma-NOS by immunohistochemistry. Blood 134:2159-2170, 2019
30. Oon ML, Lim JQ, Lee B, et al: T-Cell Lymphoma Clonality by Copy Number Variation Analysis of T-Cell Receptor Genes. Cancers (Basel) 13:340, 2021
31. Wai 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 107:1864-1879, 2022
32. Lim 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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