peripheral t-cell lymphomas - columbia university · 2018-11-15 · extranodal nk-/t-cell lymphoma,...
TRANSCRIPT
Teresa Palomero, PhD
Institute for Cancer Genetics
Department of Pathology and Cell Biology
Herbert Irving Comprehensive Cancer Center
Columbia University Medical Center
Peripheral T-cell Lymphomas
T-lymphocytes control cell-mediated adaptive immunity
(adapted from Buck et al., JEM 2015)
T-cell differentiation is a complex process
v
v
v
(Debock and Flammand, Frontiers Immunol 2015)
The generation of complete T-cell repertoir is
associated with specific transcriptional programs
(adapted from de Leval and Gaulard, ASH Education, 2008)
T-cell lymphoma derive from the malignant
transformation of mature T-cells
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*
The complexity of Peripheral T-cell Lymphomas (PTCL)
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.
Geographic diversity and incidence of PTCL
PTCL is associated with poor prognosis
Adapted from Abouyabis et al., Leukemia & Lymphoma (2008) and Vose et al., J Clin Oncol (2008)
Ove
rall
su
rviv
al (%
)
Time (years)
Age a
dju
ste
d incid
ence r
ate
Year of Diagnosis
Improvement is on B-cell lymphoma
No improvement in clinical outcome PTCL
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
Molecular Pathogenesis of Peripheral T cell lymphoma
Molecular analysis of nodal PTCL: importance
for classification and cell of origin
(adapted from de Leval and Gaulard, ASH Education, 2008)
IDH2
NH2 452
R1
72
K
DNMT3A
D7
02
N
L6
50
Q
N8
38
D
R7
36
C
R8
82
H
V6
90
D
NH2 PHD Methyltransferase 912
L6
48P
N8
79D
PWWP
RHOA
G1
7V
,G
17
EC
16
R
D1
20
Y
CAAXNKxD
NH2
TET2
Cys DSBH 2002
S1
87
0L
C12
21
Y
L1
34
0R
L137
8F
H1
38
0L
H18
81
R
C12
73
F
S1
89
8F
T1
9I
NH2 GG Effector 193
CD28
NH2 220
D124E
,D
124V
NH2 537
R1
76
C
Immunoglobulin domain
T195P
,T
195I
FYN
SH2SH3 Kinase domain
Y5
31
H
L1
74
R
TML S2
S3
Recurrent alterations in epigenetic regulators in PTCL
TET2 and DNMT3A loss of function mutations in PTCL
Incidence of TET2 mutations
(Chiba, 2017)
(Couronne et al., NEJM 2012)
IDH2 mutations in AITL
IDH2
NH2 452
R1
72
K
DNMT3A
D7
02
N
L6
50
Q
N8
38
D
R7
36
C
R8
82
H
V6
90
D
NH2 PHD Methyltransferase 912
L6
48P
N8
79D
PWWP
RHOA
G1
7V
,G
17
EC
16
R
D1
20
Y
CAAXNKxD
NH2
TET2
Cys DSBH 2002
S1
87
0L
C12
21
Y
L1
34
0R
L137
8F
H1
38
0L
H18
81
R
C12
73F
S1
89
8F
T1
9I
NH2 GG Effector 193
CD28
NH2 220
D124E
,D
124V
NH2 537
R1
76
C
Immunoglobulin domain
T195P
,T
195I
FYN
SH2SH3 Kinase domain
Y5
31
H
L1
74
R
TML S2
S3
PTCL, an example of an epigenetic-driven disease
(De Lera and Ganesan, Clinical Epigenetics 2016)
PTCL, NOS, a miscellaneous group
(Iqbal et al., Blood Reviews 2016)
Anaplastic Large Cell Lymphoma and subtypes
(Mosse et al., CCR 2009)
(Parrilla Castellar et al., Blood 2014)
(Mereu et al., Oncotarget 2016)
Anaplastic Large Cell Lymphoma, ALK negative
(Crescenzo et al., Cancer Cell 2016)
ALCL, opportunities for therapy
(Werner et al., Cancers 2017)
(Gambacorti-Passerini et al., Am J Hematol 2018)
Angioimmunoblastic T-cell Lymphoma (AITL) is
derived from T-follicular helper cells
(Cortes and Palomero, 2016)
(de Leval and Gaulard, ASH Education 2008)
Activating mutations in the TCR pathway in AITL
(Vallois et al., Blood 2016)
(Rohr et al., Leukemia 2016)
Activating FYN kinase mutations in PTCL
P-SRC
Structure modeling of PTCL FYN mutations
P
SH2
SH3
CSK
SH3
SH2
InactiveActive
Inhibition of oncogenic mutant FYN activity by Dasatinib
Dasatinib (BMS-354825)
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
RHOA G17V impairs RHOA activation by
interfering with RHOA pathway activation
• Cytoskeleton remodeling
• Migration
• Receptor signaling regulation
F-ACTIN
ROCK
RHO-GEF
RHOA
RHO-GAP
RHOA
RHOA
G17V
P
GTP
GTPGDP
CD28
CD3
FYNLCKZAP70
TCR CD4
Ga b
g
RHOA G17V
• does not upload GTP
• does not interact with effectors
• has high affinity for RHO-GEFs
Tamoxifen-induced expression of Rhoa G17V
in CD4+ cells leads to TFH differentiation
Rhoa G17V affects preferentially TFH specification
Developing a bone marrow transplant model to study
RHOA G17V lymphomagenesis
Expression of RHOA G17V in a Tet2 null
background leads to AITL development
Tet2-/- RHOA G17 mouse models as a platform for
experimental therapeutics
Palatrexate
5-Aza
ICOS blockade inhibits AITL growth in vivo
Duvelisib inhibits AITL growth in vivo
RHOA G17V Induces T Follicular Helper Cell Specification
and Promotes Lymphomagenesis
(Cortes et al., 2018)
AITL PTCL−NOS ALCL NK
VAV1ALK
CREBBPCCND3STAT6
STAT5BJAK1
STAT3TP53
PRDM1PLCG1
VAV1ATM
CARD11DNMT3A
FYNCD28IDH2TET2
RHOA
Gene fusions
Mutations
FrameshiftStop gainMissenseIn-frame deletionIn-frame gene fusion
Identification of frequent alterations in VAV1 in PTCL
(Abate and da Silva Almeida et al, PNAS 2017)
CH Ac DH PH C1 SH3 SH2 SH3 845NH2VAV1
941NH2 CH Ac DH PH C1 SH3 SH2VAV1-THAP4 nitrobindin
VAV1 THAP4
A GA GA A CCATCA GCA GGCCA GCA GA GCCCCCCA A GATGA A CCCA GTG
VAV1 MYO1F
A GA GA A CCATCA GCA GGCCA GCA GA GCC TA CGCGGA A GGGA ATGGCC
952NH2 CH Ac DH PH C1 SH3 SH2 SH3VAV1-MYO1F
884NH2 CH Ac DH PH C1 SH3 SH2VAV1-S100A7 EF1 EF2
A GA GA A CCATCA GCA GGCCA GCA GGCT T T T TGA A A GCA A A GATGA GCA A
VAV1 S100A7
A
B
C
D
C-terminal VAV1 gene fusions in PTCL
(Abate and da Silva Almeida et al, PNAS 2017)
VAV1 splice site deletions induce alternative splicing
by eliminating an exonic silencer
Deletions affecting the c-terminal SH3 domain of VAV1
induce an open active conformation of the protein
SL
P7
6
PI3K
PKC
PLCg
NFAT
CALCN
NFkB
RAC1
MAPK
RAS
DAG
IP3
Ca2+
• Cytoskeleton remodeling
• Migration
• Receptor signaling regulation
FYN*
LCK
LA
T
ITK
NCK
GADSSOS
GRB2PKCq
RASGRP1
AP1
IKB
STAT3
ADAP
JNKPAK
ZAP70 VAV1*
PAK
Ca2+CD28*
TCR
CD3
CD4
Plasma membrane
Nucleus
• Transcription
• Cell growth
• Effector function
• Survival
F-ACTIN
Kinase
RhoGAP
RHOA
*
ROCK
TCR signaling pathways play a key role in AITL
ICOS
Mutational landscape of CTCL and Sezary Syndrome
TP53
TP53 inactivation in CTCL
(da Silva Almeida, Abate et al., 2015)
Mutations in epigenetic regulators in CTCL
(da Silva Almeida, Abate et al., 2015)
Activating mutations in signaling pathways in CTCL
(da Silva Almeida, Abate et al., 2015)
PRKG1 mutations impair dimerization and increase NFAT activation
(da Silva Almeida, Abate et al., 2015)
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
New insights into experimental therapeutics
Mi-2Bortezomib
TofacitinibRuxolitinib
FK506
U0126
VorinostatRomidepsin
MechloretamineChlorambuciletoposide
PRKG1
Ca2+
(da Silva Almeida, Abate et al., 2015)
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.
