Peripheral T-cell Lymphomas

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1 Peripheral T-cell Lymphomas Teresa Palomero, PhD Institute for Cancer Genetics Department of Pathology and Cell Biology Herbert Irving Comprehensive Cancer Center Columbia University Medical Center

2 T-lymphocytes control cell-mediated adaptive immunity

3 T-cell differentiation is a complex process v v v (adapted from Buck et al., JEM 2015)

4 The generation of complete T-cell repertoir is associated with specific transcriptional programs (Debock and Flammand, Frontiers Immunol 2015)

5 T-cell lymphoma derive from the malignant transformation of mature T-cells (adapted from de Leval and Gaulard, ASH Education, 2008)

6 The complexity of Peripheral T-cell Lymphomas (PTCL) MATURE T AND NK NEOPLASMS (WHO 2016 UPDATED CLASSIFICATION) T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK cells Aggressive NK-cell leukemia Systemic EBV+ T-cell lymphoma of childhood* Hydroa vacciniforme like lymphoproliferative disorder* Adult T-cell leukemia/lymphoma Extranodal NK-/T-cell lymphoma, nasal type Enteropathy-associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphoma* Indolent T-cell lymphoproliferative disorder of the GI tract* Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous γδ T-cell lymphoma Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Primary cutaneous acral CD8+ T-cell lymphoma* Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder* Peripheral T-cell lymphoma, NOS Angioimmunoblastic T-cell lymphoma Follicular T-cell lymphoma* Nodal peripheral T-cell lymphoma with TFH phenotype* Anaplastic large-cell lymphoma, ALK+ Anaplastic large-cell lymphoma, ALK * Breast implant associated anaplastic large-cell lymphoma* Non-Hodgkin's Lymphomas caused by malignant T-Cell lymphocytes represent a smaller subset (about 15% in the US) of the known types of non--hodgkin's lymphoma - approximately 6,885 new cases diagnosed annually.

7 Geographic diversity and incidence of PTCL

8 PTCL is associated with poor prognosis Age adjusted incidence rate Overall survival (%) Time (years) Improvement is on B-cell lymphoma No improvement in clinical outcome PTCL Year of Diagnosis Adapted from Abouyabis et al., Leukemia & Lymphoma (2008) and Vose et al., J Clin Oncol (2008)

9 Current challenges in Peripheral T cell lymphoma No specific treatment tailored for PTCL Heterogeneous and rare nature of the disease allows for limited scope studies Poor understanding of molecular pathogenesis Lack of disease models (cell lines and animal models) for modeling disease and develop experimental therapeutics Limited targeted therapies available

10 Molecular Pathogenesis of Peripheral T cell lymphoma

11 Molecular analysis of nodal PTCL: importance for classification and cell of origin (adapted from de Leval and Gaulard, ASH Education, 2008)

12 D124E, D124V T195P, T195I R172K L648P L650Q V690D D702N R736C N838D N879D R882H C1221Y C1273F L1340R L1378F H1380L S1870L H1881R S1898F C16R T19I D120Y G17V, G17E Recurrent alterations in epigenetic regulators in PTCL RHOA NH2 G Effector G NKxD CAAX 193 TET2 NH2 Cys DSBH 2002 DNMT3A NH2 PWWP PHD Methyltransferase 912 IDH2 NH2 452 CD28

13 TET2 and DNMT3A loss of function mutations in PTCL (Chiba, 2017) Incidence of TET2 mutations (Couronne et al., NEJM 2012)

14 RHOA IDH2 mutations NH2 in AITL G C16R T19I G Effector NKxD CAAX 193 D120Y TET2 C1221Y C1273F L1340R L1378F H1380L S1870L H1881R S1898F NH2 Cys DSBH 2002 DNMT3A L648P L650Q V690D D702N R736C N838D N879D R882H NH2 PWWP PHD Methyltransferase 912 IDH2 R172K NH2 452 CD28 D124E, D124V T195P, T195I NH2 Immunoglobulin domain L TM S2 220 S3 FYN L174R R176C Y531H NH2 SH3 SH2 Kinase domain 537

15 PTCL, an example of an epigenetic-driven disease (De Lera and Ganesan, Clinical Epigenetics 2016)

16 PTCL, NOS, a miscellaneous group (Iqbal et al., Blood Reviews 2016)

17 Anaplastic Large Cell Lymphoma and subtypes (Mereu et al., Oncotarget 2016) (Parrilla Castellar et al., Blood 2014) (Mosse et al., CCR 2009)

18 Anaplastic Large Cell Lymphoma, ALK negative (Crescenzo et al., Cancer Cell 2016)

19 ALCL, opportunities for therapy (Gambacorti-Passerini et al., Am J Hematol 2018) (Werner et al., Cancers 2017)

20 Angioimmunoblastic T-cell Lymphoma (AITL) is derived from T-follicular helper cells (Cortes and Palomero, 2016) (de Leval and Gaulard, ASH Education 2008)

21 Activating mutations in the TCR pathway in AITL (Vallois et al., Blood 2016) (Rohr et al., Leukemia 2016)

22 Activating FYN kinase mutations in PTCL P-SRC

23 Structure modeling of PTCL FYN mutations SH3 CSK SH2 SH3 SH2 Active P Inactive

24 Inhibition of oncogenic mutant FYN activity by Dasatinib Dasatinib (BMS )

25 Recurrent mutations in RHOA in PTCL Palomero et al., Nat Genet 2014 Sakata-Yanagimoto et al., Nat Genet 2014 Yoo et al., Nat Genet 2014

26 RHOA G17V impairs RHOA activation by interfering with RHOA pathway activation TCR CD4 CD28 CD3 ZAP70 LCK FYN G a b g RHOA G17V does not upload GTP does not interact with effectors has high affinity for RHO-GEFs GTP RHO-GEF RHOA G17V F-ACTIN RHOA GDP RHOA GTP Cytoskeleton remodeling Migration Receptor signaling regulation P RHO-GAP ROCK

27 Tamoxifen-induced expression of Rhoa G17V in CD4+ cells leads to TFH differentiation

28 Rhoa G17V affects preferentially TFH specification

29 Developing a bone marrow transplant model to study RHOA G17V lymphomagenesis

30 Expression of RHOA G17V in a Tet2 null background leads to AITL development

31 Tet2 -/- RHOA G17 mouse models as a platform for experimental therapeutics Palatrexate 5-Aza

32 ICOS blockade inhibits AITL growth in vivo

33 Duvelisib inhibits AITL growth in vivo

34 RHOA G17V Induces T Follicular Helper Cell Specification and Promotes Lymphomagenesis (Cortes et al., 2018)

35 Identification of frequent alterations in VAV1 in PTCL Gene fusions ALK VAV1 Mutations RHOA TET2 IDH2 CD28 FYN DNMT3A CARD11 ATM VAV1 PLCG1 PRDM1 TP53 STAT3 JAK1 STAT5B STAT6 CCND3 CREBBP AITL PTCL NOS Frameshift Stop gain Missense In-frame deletion In-frame gene fusion (Abate and da Silva Almeida et al, PNAS 2017)

36 C-terminal VAV1 gene fusions in PTCL A VAV1 NH2 CH Ac DH PH C1 SH3 SH2 SH3 845 B VAV1-S100A7 NH2 CH Ac DH PH C1 SH3 SH2 EF1 EF2 884 VAV1 S100A7 A GA GA A CCATCA GCA GGCCA GCA GGCT T T T TGA A A GCA A A GATGA GCA A C VAV1-THAP4 NH2 CH Ac DH PH C1 SH3 SH2 nitrobindin 941 VAV1 THAP4 A GA GA A CCATCA GCA GGCCA GCA GA G CCCCCC A A G A TGA A CCC A G TG D VAV1-MYO1F NH2 CH Ac DH PH C1 SH3 SH2 SH3 952 VAV1 MYO1F A GA GA A CCATCA GCA GGCCA GCA GA G CC TA CG CG G A A G G G A A T G G CC (Abate and da Silva Almeida et al, PNAS 2017)

37 VAV1 splice site deletions induce alternative splicing by eliminating an exonic silencer

38 Deletions affecting the c-terminal SH3 domain of VAV1 induce an open active conformation of the protein

39 TCR signaling pathways play a key role in AITL ITK LAT SLP76 TCR CD4 ICOS CD28* Ca2+ CD3 Plasma membrane ZAP70 Kinase RhoGAP RHOA * ROCK LCK FYN* RAC1 PAK PI3K F-ACTIN PLCg VAV1* NCK GADS GRB2 ADAP SO S PAK DAG RA S RASGRP1 IP3 PKC PKCq IKB JNK MAPK NFkB AP1 Ca2+ CALCN NFAT Cytoskeleton remodeling Migration Receptor signaling regulation STAT3 Transcription Cell growth Effector function Nucleus Survival

40 Mutational landscape of CTCL and Sezary Syndrome

41 TP53 inactivation in CTCL TP53 (da Silva Almeida, Abate et al., 2015)

42 Mutations in epigenetic regulators in CTCL (da Silva Almeida, Abate et al., 2015)

43 Activating mutations in signaling pathways in CTCL (da Silva Almeida, Abate et al., 2015)

44 PRKG1 mutations impair dimerization and increase NFAT activation (da Silva Almeida, Abate et al., 2015)

45 Frequent mutations affecting the NFkB pathway in CTCL (da Silva Almeida, Abate et al., 2015) Vaque et al., Blood 2014 Choi et al., Nat Genet 2015 Kiel et al., Nat Commun 2015 Ungewickell et al., Nat Genet 2015 Da Silva Almeida, Abate et al., Nat Genet 2015

46 New insights into experimental therapeutics Ca2+ PRKG1 Tofacitinib Ruxolitinib Mi-2 Bortezomib U0126 FK506 Mechloretamine Chlorambucil etoposide Vorinostat Romidepsin (da Silva Almeida, Abate et al., 2015)

47 Conclusions PTCL are a very heterogeneous group of rare lymphoid malignancies that derive from the transformation of mature T-cells. PTCL are generally associated with advanced age, poor response to conventional chemotherapy and dismal prognosis. Introduction of precision medicine approaches has substantially improved our understanding of the classification, cell of origin and genomic vulnerabilities specific of PTCL subtypes. Epigenetic drugs have been introduced as treatment for refractory/relapsed PTCL with promising results. Other targeted therapies with variable success rate include PI3K inhibitors, ALK inhibitors and immunotherapy approaches, including anti CD30 antibodies.

48 Teresa Palomero, PhD Institute for Cancer Genetics ICRC Rm 401B