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Aplasies médullairesPhysiopathologie; Comment les diagnostiquer et les
suivre au laboratoire ?
Jean Soulier, M.D. Ph.D.
Saint-Louis Hospital
Paris, France
DES Hématologie
16 Mars 2018
Bone marrow failure (BMF) syndromes
Deficient hematopoietic stem cells (HSC)
- Manifest as cytopenia in one or more lineages
- Bone marrow: decreased cellularity (aplastic anemia) <30% related to age
890
PA
RT 7
Oncology and H
ematology
the intermediates may be genetically determined and apparent only
on specific drug challenge; the complexity and specificity of the
pathways imply multiple susceptibility loci and would provide an
explanation for the rarity of idiosyncratic drug reactions.
Immune-mediated injury
The recovery of marrow function in some patients prepared for
bone marrow transplantation with antilymphocyte globulin (ALO)
first suggested that aplastic anemia might be immune mediated.
Consistent with this hypothesis was the frequent failure of simple
bone marrow transplantation from a syngeneic twin, without con-
ditioning cytotoxic chemotherapy, which also argued both against
simple stem cell absence as the cause and for the presence of a
host factor producing marrow failure. Laboratory data support an
important role for the immune system in aplastic anemia. Blood and
bone marrow cells of patients can suppress normal hematopoietic
progenitor cell growth, and removal of T cells from aplastic anemia
bone marrow improves colony formation in vitro. Increased num-
bers of activated cytotoxic T cell clones are observed in aplastic ane-
mia patients and usually decline with successful immunosuppressive
therapy; cytokine measurements show a TH1 immune response
[interferon g (IFN g) and tumor necrosis factor (TNF)]. Interferon
and induce Fas expression on CD34 cells, leading to apoptotic cell
death; localization of activated T cells to bone marrow and local
production of their soluble factors are probably important in stem
cell destruction.
Early immune system events in aplastic anemia are not well
understood. An oligoclonal, T cell response implies an antigenic
stimulus. Many different exogenous antigens appear capable of
initiating a pathologic immune response, but at least some of
the T cells may recognize true self-antigens. The rarity of aplastic
anemia despite common exposures (medicines, seronegative hepa-
titis) suggests that genetically determined features of the immune
response can convert a normal physiologic response into a sus-
tained abnormal autoimmune process, including polymorphisms in
histocompatibility antigens, cytokine genes, and genes that regulate
T cell polarization and effector function.
CLINICAL FEATURES
History
Aplastic anemia can appear with seeming abruptness or have a
more insidious onset. Bleeding is the most common early symp-
tom; a complaint of days to weeks of easy bruising, oozing from
the gums, nose bleeds, heavy menstrual flow, and sometimes
petechiae will have been noticed. With thrombocytopenia, mas-
sive hemorrhage is unusual, but small amounts of bleeding in
the central nervous system can result in catastrophic intracranial
or retinal hemorrhage. Symptoms of anemia are also frequent,
including lassitude, weakness, shortness of breath, and a pound-
ing sensation in the ears. Infection is an unusual first symptom
in aplastic anemia (unlike in agranulocytosis, where pharyngitis,
anorectal infection, or frank sepsis occur early). A striking feature
of aplastic anemia is the restriction of symptoms to the hema-
tologic system, and patients often feel and look remarkably well
despite drastically reduced blood counts. Systemic complaints
and weight loss should point to other etiologies of pancytopenia.
Prior drug use, chemical exposure, and preceding viral illnesses
must often be elicited with repeated questioning. A family history
of hematologic diseases or blood abnormalities, and of pulmonary
or liver fibrosis, may indicate a constitutional etiology of marrow
failure.
A B
C D
Figure 107-1 A. Normal bone marrow biopsy. B. Normal bone marrow
aspirate smear. The marrow is normally 30–70% cellular, and there is a
heterogeneous mix of myeloid, erythroid, and lymphoid cells. C. Aplastic
anemia biopsy. D. Marrow smear in aplastic anemia. The marrow shows
replacement of hematopoietic tissue by fat and only residual stromal and
lymphoid cells.
Copyright © 2012 The McGraw-Hill Companies, Inc. All rights reserved.
Bone marrow failure (BMF) syndromes
Origin
- Acquired (toxic, autoimmune, hepatitis, etc.)
- Genetic: Inherited (IBMF)
- frequent dysplastic BM cells: overlap
between AA and hypocellular MDS
- predisposition to karyotype abnormalities
(monosomy 7, 5q-) and overt MDS and
AML
Deficient hematopoietic stem cells (HSC)
- Manifest as cytopenia in one or more lineages
- Bone marrow: decreased cellularity (aplastic anemia)
- frequent dysplastic BM cells: overlap
between AA and hypocellular MDS
- predisposition to karyotype abnormalities
(monosomy 7, 5q-) and overt MDS and
AML
Deficient hematopoietic stem cells (HSC)
- Manifest as cytopenia in one or more lineages
- Bone marrow: decreased cellularity (aplastic anemia) <30% related to age
Inherited Bone Marrow Failure syndromes
Syndromes Genes MDS/AML risk
Fanconi anemia FANC genes (DNA repair) 30-40%
Dyskeratosis congenita Telomere genes (TERC…) > 5%
Diamond-Blackfan anemia Ribosome genes (RPL5…) 0.5-1%
Shwachman-Diamond SBDS 10%
Severe congenital neutropenia ELANE, GFI1, others 20%
Familial platelet disorder with RUNX1 20-60%
propensity to myeloid malignancies
(FPD/AML)
Familial MDS, monoMAC GATA2 High
New/rare syndromes SRP72, DNAJC21, SAMD9/9L ?
ERCC6L2
Unidentified syndromes (?) ? ?
Hematopoietic
genes
Hematopoietic cell pool contraction and clone selection (aging, BMF)
Classic AML model with a initiating driver event such as t(8;21),
NPM1mut, MLL
In a background of HSC defect (whatever the cause), any clone
that is more fit will get an advantage
Clonal hematopoiesis according to age
From Xie et al., Jaiswal et al., Genovese et al., McKerrell et al.,
Malcovati et al.,
DNMT3A
TET2
JAK2
ASXL1
TP53
SF3B1
The Bone Marrow Failure Center at
Saint-Louis and R. Debré Hospitals, Paris
Clinical cohorts (R. Peffault de Latour, T. Leblanc, J.H. Dalle, G. Socié)
Centralized biological diagnosis of Fanconi anemia (>300 pts) and other
IBMFs
BM follow up, longitudinal sampling, translational research
Saint-Louis Hospital Robert Debré Hospital Institute of Hematology, IUH St-Louis
Saint-Louis Hospital
Maladie de Fanconi (FA)
Mutations bialléliques d’un gène FANC
FANCA, FANB…, FANCW.
Maladie autosomique récessive (sauf très rare groupe FA-B lié à l’X)
La plus fréquente des aplasies génétiques
1. Syndrome congénital variable: petite taille, visage, pouce(s), tâches cutanées, reins…
2. Insuffisance médullaire d’apparition progressive; HbF et aFP élevées
3. Prédisposition au cancer: myélodysplasies, leucémies aiguës, cancers épithéliaux
FANC genes mutations in the French cohort
FANC-A 200 74,60% FA core
FANC-G 21 7.8 % FA core
FANC-D2 13 4.8 % D2
FANC-L 8 3% FA core
FANC-C 6 2.2 % FA core
FANC-F 4 1.5 % FA core
FANC-I 4 1.5 % FA core
FANC-B 4 1.5 % FA core
FANC-D1/BRCA2 4 1.5 % downstream
FANC-M 3 1.5 % FA core
FANC-T/UBE2T 1 0.4% FA core
FANC-V/REV7/MAD2L2 1 0.4% downstream
FANC-J/BRIP1 0 - downstream
FANC-N/PALB2 0 - downstream
FANC-O/RAD51C 0 - downstream
FANC-P/SLX4 1 - downstream
FANCQ/XPF/ERCC4 0 - downstream
FANC-R/RAD51 0 - downstream
FANC-S/BRCA1 0 - downstream
FANC-U/XRCC2 0 - downstream
Unidentified 0 0
Sanger and MLPA screen for mutations and deletion (fibro gDNA)
ICL blocks the
replication fork
FA core complex
signals the damage
Nucleases cut and ‘unhook’ the ICL
(Klein Douwell 2014)
The FA pathway is involved in theclearance of the DNA ICLs
>23 FA genes
(Joenje; D’Andrea;
Smogorzewska and
others1989-2016)
TLS bypass (Knipscheer 2009)REV7/FANCV
HR
endogeneous
aldehydes
(Langevin 2011)
REV7/FANCV
(Bluteau 2016)
"downstream"
FA genes
Nearly half of the Japanese population carries a dominant-negative allele
G/A of the aldehyde-catalyzing enzyme ALDH2
Is severe BMF more early in AA or A/G patients compared to GG ?
Flush syndrom
to ethanol
Natural confirmation in Human
Blood , Sept 2013
BMF cumulative prevalence in FA patients
At birth Aplasia PreleukemiaLeukemia
at diagnosismyélodysplasia
Most patients develop BMF during childhood
30% of the patients will develop myelodysplasia or leukemia < 30 yo
Bone marrow progression in FA
What are the mechanisms
of the stem cell defect in FA ?
Unresolved DNA damage and p53-p21 activation
in FA HPCs
p53 silencing partially rescued FA cells
- In vitro CFU-GM
- Engraftment in a humanized model
But more genomic instability
ShRNA FANCD2
ShRNA FANCD2-TP53-GFP
Immunodeficient
mice
Ceccaldi et al., Cell Stem Cell 2012
Heathy
bone marrow
FA patients
bone marrow
SKP2
CDKN1B/p27
CDKN1A/p21
CDKN2D/p19
CDKN2C/p18
CDKN2A/p16
CDKN3
CDC7
CDK4
DBF4
CUL3
CUL1
S phase
S phase inhibitors
including
CDKN1A/p21
G1_S transition of the mitotic cell cycle
S phase
S phase
inhibitors
Senescence, G1_S arrest
Hu cord blood
CD34+ cells
sh FANCD2 sh FANCD2-
TP53
% b
loo
d G
FP
+c
ells
0
10
20
30
40*
Chimerism
in mice
Sh FANCD2 shFANCD2-TP53Sh FANCD2 shFANCD2-TP53
BM
from patients
P53 IFH2AX foci in the
BM cells
% o
f G
FP
+ c
ells
Inflammation (pI:pC injection) triggers
HSC cycling and DNA damage, the repair
of which involves the FA pathway
In FA-deficient mice, unresolved damage
leads to HSC apoptosis and to BMF
Nature 2015
FANCD2 foci
PSp/AGM
Yolk sac
Fetal liver
Bone marrow
Spleen
Thymus
987 10 11 12 13 14 1615 2117 18 19 20 JPC
Birth
Primitivehematopoiesis Placenta
AGM
YS
Pl
FLFL T
Circulation
DéfinitiveHematopoiese
HSC expansion in the liver
Hematopoietic ontogeny (mouse)
♀ Fancg+/- x ♂ Fancg+/-
<1/4 Fancg-/- embryos (155/838 alive)
WT Fancg -/-
1 mm 1 mm
FL FL
n =91n =139
**
E12.5 Fancg-/- embryos, placentas and liverswere smaller than WT, contrasting with newbornand adult mice and organs
Deficiency of the fetal HSC functions in in vitro and in vivo experiments (LT-CIC, primary and secondary competitive transplants)
Embryos
Placentas n =139 n =91*
Fetal livers n =139 n =91***
1 mm 1 mm
1 mm 1 mm
Halfon et al., ASH 2015
Defects in Fancg-/- mouse embryos
Pre-natal begining of the hematopoietic defect in FA
Replicative stressaldehydes
DNA damagecellular stress
Poor HSC pool
Aging, Bonemarrow failure
Impairment of HSC pool expansion
Fetal liver
ChildhoodDNA damage response geneset
Cdkn1a/p21
- Analysis of medical diagnosis
samples after termination of birth of
FA fetuses (with informed consent; in
accordance with French laws)
Ceccaldi et al., 2012
P Kurre, 2013
Halfon et al., ASH 2015
aplasiaImpaired
expansion of the HSC pool
decreased
pool at birth
Replicative stressaldehydes
DNA damagecellular stress
Poor HSC pool
Aging, Bonemarrow failure
Impairment of HSC pool expansion
Fetal liver
Childhood
Natural history of BM progression in FA
Somatic
mosaicism
Genetic
reversion
Lo Ten Foe., Eur J Genet 1997
Waisfisz, Nat Genet 1999
Soulier, Blood 2005
15% of patients;
mild or normal blood counts;
NOT seen in skin fibroblasts
MDS AML
Germline
FANC
mutation
CLONAL EVOLUTION
Replicative stressaldehydes
DNA damagecellular stress
Poor HSC pool
Aging, Bonemarrow failure
Impairment of HSC pool expansion
Fetal liver
Childhood
CLONAL EVOLUTION
aplasiaImpaired
expansion of the HSC pool
Clones MDS/AML decreased
pool at birth
Natural history of BM progression in FA
Germline
FANC
mutation
MDS: refractory cytopenia with multilineage dysplasia (RCMD), w or w/o excess of blasts
(RAEB). AML can be diagnosed de novo or (more often) following a MDS phase
‘secondary-like’ leukemia.
- No classical translocations like t(8;21) or MLL
- Frequent translocations involving 1q, 3q, and 7q
Chr. 1 Chr. 3 Chr. 10
F, 21 yo, AML
46,XX,der(10)t(3;10)(q23;q26),der(13)t(1;13)(q10;p10) [20]
Gross chromosomal abnormalities with copy number gain/losses
Short deletions;translocations
RUNX150 Kb
1q+
3q+
Very frequent unbalanced translocations in MDS/AML cellsfrom FA patients
Patient EGF117
EGF015
der(4)t(1;4)(q21;p16)
Post-replicative break Translocation 1q
Mitosis
1q+ cell with
survival advantage
Cell death
(Alt)-NHEJ
EGF015
der(4)t(1;4)(q21;p16)
Post-replicative break Translocation 1q
Mitosis
1q+ cell with
survival advantage
Cell death
(Alt)-NHEJ
Quentin, Blood 2011
1q+
Chr.1 Chr.2 Chr.3 Chr.4 Chr.5 Chr.6 Chr.7 Chr.8 Chr.9 Chr.10
Chr.11 Chr.13 Chr.16 Chr.17 Chr.18 Chr.19 Chr.20 Chr.21 Chr.XChr.22Chr.12 Chr.14 Chr.15 Chr.Y
RUNX1
A recurrent pattern of acquired chromosomal
abnormalities in the bone marrow cells of FA patients
gain loss UPD
Chr.1 Chr.2 Chr.3 Chr.4 Chr.5 Chr.6 Chr.7 Chr.8 Chr.9 Chr.10
Chr.11 Chr.13 Chr.16 Chr.17 Chr.18 Chr.19 Chr.20 Chr.21 Chr.XChr.22Chr.12 Chr.14 Chr.15 Chr.Y
RUNX1
A recurrent pattern of acquired chromosomal
abnormalities in the bone marrow cells of FA patients
gain loss UPD
RUNX1
MDM4
EVI1 -7q
RUNX1
3q+
Normal MDS AML
48 months
29 y. 33 y.
Patient EGF089
Longitudinal analysis in FA patients: +1q is an early event
What is the order of the genomic events ?
Birth AplasiaClonal
hematopoiesis MDS RAEB/AML
1q+/MDM4 3q+/EVI1
PRDM16
-7q
21q/RUNX1
RAS pathways
HSPC
expansion?Blast cellsSurvival
DDR attenuation
A model of the somatic landscape of
BM progression in FA
Decreased pool at birth
genomic instability
Inflammation
p53/p21 induction and TGFb induction
HSC exhaustion
Mechanism of instability is Alt-EJ or NHEJ repair of post-replicative breaks
leading to unbalanced tranlocations/deletions and CNA
Replicative stressaldehydes
DNA damagecellular stress
Poor HSC pool
Aging, Bonemarrow failure
Impairment of HSC pool expansion
Fetal liver
Childhood
Germline
FANC
mutation
Birth AplasiaClonal
hematopoiesis MDS RAEB/AML
1q+/MDM4 3q+/EVI1
PRDM16
-7q
21q/RUNX1
RAS pathways
HSPC
expansion?Blast cellsSurvival
DDR attenuation
A model of the somatic landscape of
BM progression in FA
Decreased pool at birth
genomic instability
Inflammation
p53/p21 induction and TGFb induction
HSC exhaustion
Mechanism of instability is Alt-EJ or NHEJ repair of post-replicative breaks
leading to unbalanced tranlocations/deletions and CNA
Replicative stressaldehydes
DNA damagecellular stress
Poor HSC pool
Aging, Bonemarrow failure
Impairment of HSC pool expansion
Fetal liver
Childhood
Germline
FANC
mutation HSCT
Overall survival in allogeneic HSCT in FA patients
Peffault de la Tour et al., Blood 2013
EBMT and SAA Working Party
(n=399 pts)
Cumulative incidence of death and
secondary cancers in the 1-year survivors
R. Peffault de Latour & J. Soulier, Blood 2016
Staging criteria to help decision making in FA
Inherited Bone Marrow Failure syndromes
Hematopoietic
genes
Syndromes Genes
Fanconi anemia FANC genes (DNA repair)
Dyskeratosis congenita Telomere genes (TERC…)
Diamond-Blackfan anemia Ribosome genes (RPL5…)
Shwachman-Diamond SBDS
Severe congenital neutropenia ELANE, GFI1, others
Familial platelet disorder with RUNX1
propensity to myeloid malignancies
(FPD/AML)
Familial MDS, monoMAC GATA2
New/rare syndromes SRP72, DNAJC21, SAMD9/9L
ERCC6L2
Unidentified syndromes (?) ?
Clonal evolution in a case of Severe Congenital
Neutropenia (SCN)
Exome sequencing, and deep-sequencing at several stages
Beekman, et al., Blood 2012
Familial platelet disorder with propensity to
myeloid malignancies (FPD/AML)
Germline RUNX1 mutation (Autosomic dominant)
Antony-Debré I et al., Leukemia 2016
Familial platelet disorder with propensity to
myeloid malignancies (FPD/AML)
At birth AML
2cd allele
RUNX1FLT3-ITD
KRASThrombocytopenia CDC25A ?
(Japan)
Germline RUNX1 mutation (Autosomic dominant)
- Index patient IV-1 : severe BMF at 13 months, monosomy 7 without BM dysplasia, telo NL
HSCT was planned but eventually cancelled for spontaneous improvement. Nystagmus
- His mother, III-2, similar story 31 years previously: 13 months old, AA, HSCT planned but cancelled, nystagmus, telo NL
- Her sister (III-3), transitory pancytopenia
both sisters, now aged 33 and 37 years, are doing well.
- Grand-mother(II2): ataxia but well otherwise
- Great-mother (I1): ataxia but well otherwise
Ataxia-Pancytopenia Syndrom
Mutation in the SAMD9L gene
All patients had an activating SAMD9L c.C2956T mutation
in fibroblasts or mouth brush
All had additional somatic «reversion» event in blood
(UPD, monosomy 7, or inactivating truncating mutation)
Ataxia-Pancytopenia Syndrom
Mutation in the SAMD9L gene
At birth
Monosomy 7
Inactivating
cis mutation or UPD7q
Germline SAMD9L activating mutation (autosomic dominant)
ouou
Aplasia
Recovery; no AML
orou ou
SAMD9L mut
(germline)
? MDS/AML
ou
Genomic landscape in ‘unresolved’ IBMF
B
48.0% (n=86)
17.9% (n=32)
34.1% (n=61)
Group 1 Patients Group 2 Patients Group 3 Patients
A
0
1
2
3
4
5
6
7
10
8
9
11
SA
MD
9L
ER
CC
6L2
TE
RC
GA
TA
2
CT
C1
PIE
ZO
1
SB
DS
TIN
F2
ME
CO
M
SA
MD
9
RU
NX
1
LIG
4
AS
XL1
CF
HR
3
DN
AJC
21
RT
EL1
SR
P72
AB
L2
CB
L
CH
EK
2
EN
G
TE
RT
ER
G
PA
RN
TN
FR
SF
13B
CE
BP
A
ZF
PM
1
AL
AS
2
AT
R
CD
AN
1
KIT
CF
HR
1
ET
S2
PA
X5
AB
L1
RP
L5
BC
L2L10
CL
CN
7
BR
CA
2
CF
I
DD
X41
DK
C1
ET
V6
GA
TA
1
GF
I1
GP
1B
A
MY
SM
1
ITG
A2B
MD
M2
MK
RN
1
MD
M4
PR
F1
PP
M1D
TA
L1
RP
L11
RP
L35A
SH
2B
3
SL
C3
7A
4
ST
IM1
PT
PN
11
TP
53
TP
53
BP
2
No
. o
f vari
an
ts
C
0 1 2 3 4 5 6 7 8 9 10
SAMD9L TERC
GATA2 TINF2
ERCC6L2 MECOM SAMD9 RUNX1
CTC1 SBDS
SRP72 LIG4
DNAJC21 RTEL1 TERT PARN RPL5
ALAS2 ATR
DDX41 DKC1 ETV6
GATA1 MYSM1
PRF1 RPL11
RPL35A STIM1
No. of patients with variants
D
UB
06
6U
B0
90
UB
11
7U
B2
00
UB
07
3U
B0
22
UB
13
4U
B2
62
UB
09
2U
B2
25
UB
22
7U
B2
56
UB
25
2U
B2
50
UB
02
9U
B1
31
UB
23
4U
B2
03
UB
05
6U
B2
87
UB
65
8U
B1
97
UB
26
0U
B0
62
UB
22
2U
B2
41
UB
22
1U
B0
23
UB
04
0U
B0
97
UB
10
1U
B1
05
UB
06
4U
B0
76
UB
09
3U
B0
04
UB
03
6U
B1
00
UB
10
4U
B1
53
UB
06
9U
B2
54
UB
21
5U
B0
71
UB
28
1U
B1
46
UB
13
7U
B2
24
UB
04
9U
B0
85
UB
19
5U
B6
09
UB
61
2U
B0
81
UB
11
2U
B1
94
UB
13
6U
B0
26
UB
03
7U
B0
96
UB
66
0U
B2
83
UB
04
3U
B0
86
UB
14
5U
B0
77
UB
05
4U
B11
4U
B0
91
UB
27
4U
B6
13
U
B0
07
UB
00
8U
B2
31
UB
07
5U
B0
83
UB
19
6U
B1
68
UB
65
7U
B0
25
UB
14
3U
B1
92
UB
23
5U
B0
38
UB
28
0U
B2
75
Neutropenia
Thrombocytopenia
Anemia
# # # # # # # # # # # # #Family history
Age ≤ 2 years
Physical signs
* * * * * * * *BM dysplasia
Monosomy 7
TERC
TINF2
CTC1
TERT
RTEL1
PARN
DKC1
GATA2
MECOM
RUNX1
ETV6
GATA1
ALAS2
SAMD9L
SAMD9
SBDS
SRP72
DNAJC21
RPL5
RPL11
RPL35A
ERCC6L2
LIG4
ATR
PRF1
STIM1
DDX41
MYSM1
Probably
causal
genes
CEBPA
ABL1
ERG
ETS2
KIT
MKRN1
CHEK2
PPM1D
ENG
TNFRSF13B
Possibly
contributing
genes
SAMD9 and
SAMD9L
Telomere
function and
maintenance
Hematopoiesis
Ribosome
assembly
DNA damage
response
Immune
response
GATA2
SA
MD
9L
PRF1
SRP72
SB
DS
ER
CC
6L
2
RT
EL
1
TINF2
TERC
SA
MD
9
E
Bluteau O et al., Blood prepublished on line
The cellular pathways of IBMF
A role for extrinsic signals in IBMF ?
THPO mutations
Clinical response, not to HSCT but to TPO-R agonist
How to diagnose IBMF ?
- Phenotypic tests are useful
Chromosome breaks in all BMF patients
Telomere length
Pancreas tests
- Fibroblast cells to rule out potential reversion and confounding
somatic mutations
- Targeted sequencing
- Multigene panels with broad, updated list of IBMF/MDS genes
- Multidisciplinary roundtable sessions (RCP multidisciplinaire)
Depending on the presentation, the physician and the lab:
- Oriented screen for a classic diagnosis (FA, DBA, SDS, DC, SNC…)
- NGS
Bone Marrow Failure Department, Hôpital St-Louis and Robert
Debré, Paris - French Reference Center “Bone marrow failure ”
R Debré Hematoloy Lab
Nadia Vasquez, Mélanie Da Costa
Anna Raimbault, Wendy Cuccuini
Olivier Bluteau, Marie Sebert
Samuel Quentin, Lucie Hernandez
Dominique Bluteau, Carel Fédronie
Emmanuelle Clappier, Marie Passet
Hematology Laboratory APHP and
INSERM U944/CNRS7212
IUH – Fanconi team
Hôpital Saint-Louis, Paris
Oncogenetic Department, Institut Curie, Paris
Dominique Stoppa-Lyonnet,
Catherine Dubois d’Enghien
Yves Bertrand, Gérard Michel, Pierre Rohrlich, Stanislas
Lyonnet, Stéphane Blanche, Isabelle Pellier, Virginie
Gandemer, many others
Hematology, Pediatry and Genetic Departments Lyon, Marseille,
Angers, Nice, Necker, and many more
Institut Pasteur
Ludovic Deriano, Valentine Murigneux
Saint-Louis Hospital
INSERM IUH
Michèle Souyri, Carine Domenech
Régis Peffault de Latour, Gérard Socié, Flore Sicre
Thierry Leblanc, Jean-Hugues Dalle, André Baruchel
Lydie Da Costa, Elodie Lainey
Dana Farber Cancer Institute and Harvard
Medical School, Boston, MA, USA
Alan D’Andrea
Raphael Ceccaldi
Kalindi Parmar