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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
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
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
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
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
IDH2 Mutant is Restricted to Tumor Cells
Vallois et al. Blood 2016
IDH2R172K ICOS
CD8 IDH2R172K
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
5hmC Loss is Frequent in PTCL
IDH2 and TET2 mut AITL
5hmC
5hmC
PD1
IDH2 and TET2 WT AITL Reactive lymph node
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
5-Azacytidine Efficacy in TET2 mut AITL
Cheminant et al. BJH. 2014
Delarue, Dupuis et al.
ORR: 75%
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)
Contributors
TENOMIC