Pathogenesis of Natural Killer / T-cell Lymphoma

Transcription

1 Pathogenesis of Natural Killer / T-cell Lymphoma Prof Chng Wee Joo Provost s Chair Professor Yong Loo Lin School of Medicine, NUS Director National University Cancer Institute, Singapore Deputy Director Cancer Science Institute of Singapore, NUS Clinical Care Education Research

2 Conflict of Interest No Conflict of Interest relevant to this presentation to declare

3 Extranodal nasal-type Natural Killer/T-cell lymphoma (NKTL) Distinct clinicopathologic entity most commonly affecting Asians and Central and South Americans characterized by a clonal proliferation of NK or T cells with a cytotoxic phenotype. There is a strong association with Epstein-Barr Virus (EBV), which manifests a type II latency expression of LMP-1 and EBNA-1, absence of EBNA-2. EBV detected in the neoplastic cells in a clonal episomal form, supporting the role of the virus in tumor pathogenesis

4 Clinical Spectrum of Extra-nodal Natural Killer / T-cell Lymphoma Kwong YL. Leukemia 2005; 19:2186

5 Microarray Studies Blood 2010 J Pathol 2011 Cancer Letters 2012

6 Activation of JAK-STAT pathway Huang et al. Blood 2010

7 Activation of NFKB and MYC NKTL Cell Lines NKTL Normal NK Cells / Tissue Controls Ng SB...Chng WJ. J Pathol 2011

8 Proposed model of NKTL pathogenesis STAT MYC Regulate NF-KB P53 P53 Deregulation Induce Survivin Proliferation Anti-apoptotic

9 Sequencing Studies LOF DDX3X LOF p53 Activated STAT3/5B Jiang L et al. Nat Genet 2015

10 Recurrent Mutations DDX3X (20%) of NFKB and MAPK (Jiang L et al. Nat Genet 2015) P53 Mutation (13%) (Jiang L et al. Nat Genet 2015) STAT3/5B mutations (12%) (Jiang L, et al. Nat Genet 2015, Kucak C, et al. Nat Comms 2014) JAK3 mutation (21%-35%) (Koo GC et al. Cancer Discovery 2012; A Bouchekioua, et al. Leukemia 2014)

11 Proposed model of NKTL pathogenesis JAK3 /STAT mutations DDX3X mutations P53 mutations STAT MYC Regulate NF-KB P53 P53 Deregulation Induce Survivin Proliferation Anti-apoptotic

12 Copy Number Changes and Tumor Suppressor Gene Array CGH identity recurrent 6q Loss, (Igbal J et al. Leukemia 2009) 6q21 PRDM1 MYC (Kucuk C et al. PNAS 2011; Karube K et al. Blood 2011) 6q22 - PTPRK STAT3 (Chen Y et al, Blood 2015) Others HACE1 (known TSG) and ATG5 (Autophagy)

13 Proposed model of NKTL pathogenesis JAK3 /STAT mutations PTPRK Loss PRDM1 Loss DDX3X mutations P53 mutations STAT MYC Regulate NF-KB P53 P53 Deregulation Induce Survivin Proliferation Anti-apoptotic

14 What is the role of EBV? PLOS One 2017 Oncol Rep 2015 J Haem Onc 2016

15 Proposed model of NKTL pathogenesis JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations STAT MYC Regulate NF-KB P53 P53 Deregulation PDL1 Induce Survivin Proliferation Anti-apoptotic

16 mirna deregulation in NKTL In both NK cell lines and FFPE NKTL samples compared to normal NK cells, among the mirnas showing at least 2-fold and statistically significant difference (p<0.05) in expression: 2 upregulated (mir-155 and mir-378) 39 were down-regulated: mir-342-5p, mir-26b, mir- 363, mir-150 and mir28-5p

17 Role of MYC in mirna deregulation in NKTL

18 Relative expressions mrna expression changes upon overexpression of mirnas by Lentiviral transduction control Mir-101 control mir-26b control precursor precursor mir-26b precursor

19 EZH2 overexpression in majority of NKTL. A P=0.003 P=0.002 B

20 EZH2 is oncogenic in NKTL independent of Enzymatic Function Blood 2013

21 EZH2 overexpression in primary NK cells promotes cell growth independently of histone methyltransferase activity A C NKYS KHYG B D

22 EZH2 positively regulates CCND1 transcription by binding to its promoter in NK malignant cells A C 0.1kb CCND D B E

23 Canonical EZH2 Noncanonical GSK126 JARID2 JAK3 Y244 P EZH2 Pol II CCND1 PcG -mediated repression Transcriptional Blood 2016

24 Proposed model of NKTL pathogenesis JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

25 Potential Therapeutic Targets JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

26 Leukemia 2018

27 Potential Therapeutic Targets JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

28 Leukemia 2017

29 Potential Therapeutic Targets JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

30 Treatment of NK cell lines with survivin inhibitor

31 Potential Therapeutic Targets JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

32 Blood 2017

33 Potential Therapeutic Targets JAK3 /STAT mutations EBV infection PTPRK Loss PRDM1 Loss LMP DDX3X mutations P53 mutations JAK/STAT MYC Regulate NF-KB P53 P53 Deregulation Phophorylate mirna EZH2 PDL1 Induce Survivin Proliferation Anti-apoptotic

34 Is NKTL Homogenous Molecularly GEP on 66 cases Cluster 1: Upregulated genes loss of 14q11.2 (9/13, 69%) cases Ng SB... Haematologica 2017

35 14q11.2 loss is common event Loss (14q11.2) Loss (14q11.2) 14q11.2 overlapped the T-Cell Receptor Alpha Constant (TRAC or TCRA locus)

36 TCR loci in normal lymphocytes and PTCL TCRA locus TCRD locus Diagnosis Loss of TCR loci (n) % NK cells T cells 3/3 100 B cells 0/3 0 T cells NK cells 0/3 0 Tonsil/LN 0/3 0 PTCL 5/6 83 B cells ALCL

37 Cluster 1 is enriched for cases with nodal presentation, lack of nasal involvement and T- lineage

38 NKTL with nodal presentation showed higher T-cell signature index T-cell signature analysis was performed using genes CD27, CD3G, CD3D, ICOS, MAL, TCF7, PKIA11 (Iqbal J et al. Leukemia. 2011;25(2): )

39 Nodal NKTL cases showed distinct phenotypes

40 Nodal NKTL have distinct clinico-pathologic and molecular features Nodal Extranodal P-value Age (Std D) (15.23) (15.92) (2) Sex (F/M) 4 / / (4) Nasal involvement (Y/N) 0 / / (4) T vs NK 13 / 2 10 / (4) CD8 (Pos/Neg) 12 / 6 6 / (4) CD56 (Pos/Neg) 4 / / (4) PDL1 (tumor) (0.28) 0.75 (0.33) (3) PDL1 (normal) (0.48) 1 (0.47) (3) TCR Loss / Intact 12 / 0 7 / (4)

41 Conclusion NKTL with nodal presentation a. Associated with older age, lack nasal involvement, T cell origin, CD8+/CD2+/CD56-, high PDL1 expression a. Jeon YK, et al. Hum Pathol 2015;46(7): b. Kato S, et al. Am J Surg Pathol. 2015;39(4):

42 Acknowledgement National University Health System Ng Siok Bian Chung Tae Hoon Priyanka Maheswari, Choo Shoa Nian, Richie Soong, Anand D Jeyasekharan, Viknesvaran Selvarajan Nagoya University Hospital, Department of Pathology and Laboratory Medicine, Japan Shigeo Nakamura, Seiichi Kato Aichi Medical University Hospital, Department of Pathology Emiko Takahashi Chi-Mei Medical Center, Department of Pathology, Taiwan Chuang Shih Sung Samsung Medical Center, Sungkyunkwan University School of Medicine, Korea Ko Young Hyeh MD Anderson Cancer Center, Department of Hematopathology, Houston, USA Joseph D Khoury, C. Cameron Yin

43 Thank you for your attention NCIS Cancer Appointment Line: youtube.com/ncisnuhs fb.com/nationaluniversitycancerinstitutesingapore