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