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François Lemonnier, Institut Mondor
de Recherche Biomédicale,
INSERMU955 Equipe 9,
Créteil
Therapeutic Implications of Identification of
Mutations in Epigenetic Regulators in PTCL
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TFH Derived Peripheral T Cell Lymphomas
TFH derived PTCL= the most
frequent PTCL – Angioimmunoblastic T cell lymphomas
(AITL),
– Follicular PTCL
– Nodal PTCL with TFH phenotype
Poor outcome
Recently FDA approved drugs have
a limited efficacy
New drugs are an unmet medical
need
OS
Years
ORR Median
PFS
Pralatrexate 29% 3.5 m
Romidepsine 25% 4 m
Belinostat 25% 1.6 m
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Oncogenic Events in TFH PTCL
TFH
PTCL
RHOAG17V
(50-70%)
Epigenetic
regulators
(>70%)
Mutations in
TCR signaling
(50%)
Sakata-Yanagimoto et al, Nature genetics. 2014
TET2
IDH2R172
DNMT3A
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Objectives
Mutations in epigenetic regulators are also present in
myeloid malignancies, where 5-azacytidine is effective
IDH2 inhibitors are effective in IDH2 mutated AML
Need to identify these mutations in TFH PTCL in
clinical practice
– FFPE samples
– Tumor cells are in minority among an abundant environment
in lymph node
– TET2 and DNMT3A are not mutated in hotspot
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TENOMIC Biobank
32 centers
1020 PTCL patients (300 in clinical trials)
– Almost all with FFPE material (LYSA-P)
– 662 with frozen tissue (Tumor Biobank, Henri Mondor
university hospital)
– 550 with DNA/RNA extracted
– 30 TMAs built (LYSA-P)
– 140 with PBL DNA
– 221 (excl. ALCL) with GEP, MiRNA and aCGH
Project coordinator: V Fataccioli
CeVi collection
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IDH2 Mutant is Restricted to Tumor Cells
Vallois et al. Blood 2016
IDH2R172K ICOS
CD8 IDH2R172K
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IDH2 Mutation Identification
BM IHC
R172K 7 8
R172S 1 0
R172G 3 0
R172T 1 0
WT 14 18
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
NGS allele
specific
PCR
HRM Sanger
100 91,7
66,7 75
0 8,3
33,3 25
identifed mutation not identified mutation
IDH2R172K
-
Aurélie Dupuy
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5hmC Loss is Frequent in PTCL
IDH2 and TET2 mut AITL
5hmC
5hmC
PD1
IDH2 and TET2 WT AITL Reactive lymph node
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5hmC Loss is Frequent in PTCL
Number of cases High 5hmC in
tumor cells
High 5mC in
tumor cells
AITL 25 0 25
Mutated
AITL
14 0 14
WT AITL 11 0 11
PTCL-NOSa 10 0 10
ALK-ALCLb 3 0 3
ALK+ALCL 3 0 3
TypeI EATL 4 0 4
HSTL 3 3 3
ENKTCL 4 0 4
Total
Mut cases
WT cases
52
19
33
3
0
3
52
19
33
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5-Azacytidine Efficacy in TET2 mut AITL
Cheminant et al. BJH. 2014
Delarue, Dupuis et al.
ORR: 75%
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Perspectives
To study effect of these mutations
– In primary cells (single cell analysis)
– In mouse models (in collaboration with the group of Tak Mak,
University of Toronto)
– In PDXs models (in development)
To identify new therapeutic targets, especially in TCR
signaling
To evaluate prognostic impact of these mutations:
– Sequencing of clinical trial cohort (RAIL, REVAIL, AATT, Ro CHOP)
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Contributors
TENOMIC