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Mastocytosis
Olivier Hermine MD,PhD
CNRS UMR 8147 (Director M DY)
Service d’hématologieCentre de référence des mastocytoses
Hôpital Necker-Enfants MaladesFaculté de Médecine Necker-Cochin
Paris
Mastocytosis
Olivier Hermine MD, PhD
Hematology Department, Necker Hospital
Centre National de référence des mastocytoses, Necker Hospital
CNRS UMR 81 47
Institut Imagine, Necker HospitalInstitut Imagine, Necker Hospital
Paris, France
Centre de Référence Des MastocytosesCEREMAST
Coordonnateur
Pr Olivier HERMINE
Co-coordonnateurs
Pr Christine BODEMER
Pr Olivier LORTHOLARY
Dr Stéphane BARETE pour EMSED
Laboratoires de référence
Pr Patrice DUBREUIL - INSERM
Pr Olivier HERMINE - CNRS UMR 8147Dr Sophie GEORGIN-LAVIALLE - CNRS UMR 81 47
Dr Sylvie FRAITAG -Anatomopathologie (peau)
Dr Danielle CANIONI - Anatomopathologie (moëlle)
Dr Vahid ASNAFI - Laboratoire d'hématologie
Responsible du projet CEREMAST
Dr Olivia CHANDESRIS
Attachée de recherche clinique
Isabelle HIRSCH
Psychologue
Daniéla MOURA
Secrétaire de coordination
Anne-Florence BELLAIS
Dr Vahid ASNAFI - Laboratoire d'hématologie
Pr Serge ROMANA - Cytologie
Anesthésiste Responsable
Dr Pascale DEWACHTER
Par téléphone : 01 40 61 54 11
Par fax : 01 40 61 56 02
CEREMAST - Faculté Necker,156, Rue de Vaugirard, 75015 Paris
Mast cells are tissue cells
They are prevalent in areaswhich interface directly with
the external environmentclose to blood vessels and
Mast cells are sentinentals with strategic location
close to blood vessels andnerve endings
They can respond veryrapidy to a stimulus
with the production of awhole array of mediators
from JS. Marshall, Nature Rev Immunol 420: 787- (200 4)
Mastocytosis : DefinitionMastocytosis : Definition
-- HETEROGENEOUS GROUP OF DISORDERS CHARACTERIZED BY HETEROGENEOUS GROUP OF DISORDERS CHARACTERIZED BY ABNORMAL GROWTH AND ACCUMULATION OF MAST CELLS IN ON E ABNORMAL GROWTH AND ACCUMULATION OF MAST CELLS IN ON E OR MORE ORGANS,OR MORE ORGANS,
-- CONSIDERED AS A MYELOPROLIFERATIVE DISORDER,CONSIDERED AS A MYELOPROLIFERATIVE DISORDER,-- CONSIDERED AS A MYELOPROLIFERATIVE DISORDER,CONSIDERED AS A MYELOPROLIFERATIVE DISORDER,
-- DIVIDED INTO CUTANEOUS FORMS AND SYSTEMIC FORMSDIVIDED INTO CUTANEOUS FORMS AND SYSTEMIC FORMS
-- CLASSICAL SPONTANEOUS RESOLUTION FOR PEDIATRIC CA SESCLASSICAL SPONTANEOUS RESOLUTION FOR PEDIATRIC CASE S
-- ASSOCIATION WITH HEMATOLOGICAL DISORDERSASSOCIATION WITH HEMATOLOGICAL DISORDERS
•I - Localized•Cutaneous mastocytosis
•Mast cell sarcoma
•Extracutaneous mastocytoma
••CONSENSUS CLASSIFICATION OF MASTOCYTOSIS CONSENSUS CLASSIFICATION OF MASTOCYTOSIS ••(simplified From Valent et al, 2001)(simplified From Valent et al, 2001)
•Extracutaneous mastocytoma
•II - Generalized•Systemic mastocytosis
•- Indolent (no organ dysfunction)
•- With an AHNMD
•- Agressive (organ dysfunction)
•Mast cell leukemia (> 20%MC in BM)
PhysiopathologyPhysiopathology
MCTC MCT
SCF
����CD 34+c-kit high
MCC
IL-4SCF
?
TISSUES
IL-4Survival :SCFNGFIL-4IFN- γγγγ…...
Stem Cell CD34+Bone marrow
CIRCULATIONSCFIL-10IL-6
c-kit highFcεεεεRI negCD13+
SimplifiedSimplified pathwayspathways of of humanhuman MC MC differentiationdifferentiation
•• CC--kit activation pathwaykit activation pathway•• CC--kit activation pathwaykit activation pathway
•Lyn•Lyn
Mutations de c-kit dans les lignées cellulaires et chez les patients atteints de mastocytose
P815 souris D814Y PTFMA3 souris d573-579 JMRBL-2H3 rat D817Y PTHMC-1 humain V560G JM
D816V PT
Lignées cellulaires
ENFANT ADULTE CAS FAMILIAUX
Pas de mutationou E839K
formes extensives:D816VD816YD816F
Pas de MutationD816V/H-Systémique (80%)-Atteinte cutanée (30-50%)
V560G (rare)D820G (leukemia)
Patients avec Mastocytose
•Mastocytosis and c-Kit mutations
•Cutaneous biopsies -> RT-PCR
•Cutaneous mastocytosis UP and systemic mastocytosis
•P. Dubreuil, F Palmérini , L Nasca , (IPC Marseille - réseau AFIRMM – M Arock, O Hermine )
Augmentation de la sensibilité de détection de la mutation D816V
PCR: 2295S / 2661R
(exons 17 to 18 Fragment of 366 pb)
Ig1 Ig2 Ig3 Ig4 Ig5
TM JM TK1 TK2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
WT D816V
Digestion BsmaI
Nested-PCR amplification
Sequence
•D479N
•V560G� ∆∆∆∆418
� ∆∆∆∆564-576
•E860G� ∆∆∆∆419 (12)
•InsFF419
•C443Y•S476I
•ITD501-502(2)
•D572A•D816Y(4)
•D816I•D816V(353)
•Ig1 •Ig2 •Ig3 •Ig4 •Ig5
•TM •JM •TK1 •TK2
•1 •2 •3 •4 •5 •6 •7 •8 •9 •10 •11 •12 •13 •14 •15 •16 •17 •18 •19 •20 •21
� ∆∆∆∆417-418 D419Y
•n=603•Human mastocytosis
•Collaboration : K Hahn Houston USA
•MCL leukemia
•And Sarcoma•Systemic•Pediatric
•Ig1 •Ig2 •Ig3 •Ig4 •Ig5
•TM •JM •TK1 •TK2
•1 •2 •3 •4 •5 •6 •7 •8 •9 •10 •11 •12 •13 •14 •15 •16 •17 •18 •19 •20 •21
•Dog mast cell tumor� ∆∆∆∆826826826826−−−−828- InsDT•Q430R
•ins421 aa45
•S479I4
•N508I
•Del/Ins555-559(5)
•ITD571-590(15)
•n=88
•Team 4 : Cell Signaling, Hematopoiesis and Mechanisms of Oncogenesis
•ITD
•ITD505-508
•K509I(6)
•ITD502-503(4)
•30% of the dogs are mutated
•And Sarcoma•Systemic
•Mastocytosis 85%
•Indolent and agressive
•Pediatric
•Mastocytosis 85%
•Adultes : STAT1_3_5 • Enfants : AKT – GSK3b
•Mutations ECD and D816X signalisation
•P. Dubreuil
•Differential colony-forming ability of ECD and D816X mutants expressing Rat2 cells
•Without
•SCF
•With
•SCF•SCF
•Outcome and mutations of c-kit
Patients mastocytosisStatut of c-Kit
WTMutation autre que
D816VD816V
Children (N= 59) 15% 46% 39%
Adults (N= 485) 28% 3% 69%
•Mutation %
•age
•Mutation %
•persistent
•Mutations
•ex8 & ex9
•puberty
•Mutations
•D816V
•regressive
•50
•75
•25
•Targeting telomerase and telomeres
•AZT
•P53•P53
•Senescence
•Conséquences du raccourcissement des télomères•Catalado RT, NEJM 2009
•Crise
•Instabilité
télomérique
•Sénescence
•Télomères : taille
critique
•Cellule somatique
•p53
•pRb •Cellule
immortalisée
•Stabilisation des télomères
•Divisions cellulaires
•Taille des
télomères
•Cellule souche
•Cellule souche
Re
lati
ve t
elo
me
rase
act
ivit
y
•In Culture Mast cells dye by senescence (6 weeks)
•Telomerase activity ?
•MC
•WT
•MC
•D816V
•R
ela
tive
te
lom
era
se a
ctiv
ity
•Figure 1 : « differential expression of telomerase and telomerase activity in children and adults
mastocytosis »•B •C •D
•E •F
•A
•Children
•N=15
•Adults
•N=16
•%
hT
ER
T+
c-K
it+
ce
lls
•G
•h
TE
RT
/c-K
it m
RN
A e
xpre
ssio
n
•Children
•n=60
•Adults
•n=48
•E
•MC
•WT
•MC
•D816V
•R
ela
tive
te
lom
era
se a
ctiv
ity
•F •G
•Children n=46
•n=17•n=18 •n=11
•p = 0,043
•Fibroblastes primaires humains D816V
•DAPI •Cy3 •Merge
•Mesure de la longueur des télomères
•Par analyse FISH Cy3-(CCCTAA)3
•Fibroblastes primaires humains Del417-419 InsY
•DAPI •Cy3 •Merge
•In vitro studies in transfected fibroblasts and BMMC
•A •B
•***•*
•**
•WT •Empty •Del417/ •AY502 •D816V
•*•***
•WT •Empty •Del417/ •AY502 •D816V
•C
•WT •Empty
Vector
•Del417/
8+D419Y
•AY502
/503•D816V•WT •Empty
Vector
•Del417/
8+D419Y
•AY502
/503•D816V
•WT •EV •417 •816•502 •EV •417 •816•502
•D •E
•Mutation Val560Gly
•(JM)
•C-Kit-hTERT
•A: moelle osseuse du patient
•10 Kb
•7,4 Kb
•M L. rate
•CT sain, apparié
en âge
•TRF2
•PML
•DAPI
•Colocalisation
PML et TRF2
•Cytospin sarcome
•A: moelle osseuse du patient
•B: sarcome du patient
•D: témoins (ISM)
•C: témoin (ISM)
•Collaboration Cytogénétique Serge Romana, G Soler
•Collaboration Curie •Arturo Londono
•Role of Telomerase activity
•Mutation
•D816V
•(Exon 17)
•C-Kit
• Mastocyte Survival
•=> immortalisation
•Indolent Mastocytosis
•Télomerase activity
•Spontaneous
Regression
•Mutation
•Exons 8 à 11
•C-Kit et WT•Proliferation
•Senescence
•-No telomerase
activity
•Short telomeres
•SCF
Regression
•Tumor progression
- Instabilité génétique
- ALT
Heterogenity of diseases associated
with D816V mutations
Agressive and Hematological diseases Agressive and Hematological diseases
association vs Indolent
•5-me-Cytosine •5-hme-Cytosine
•Tet2
•Tet2 is involved in the conversion of 5 meC to 5hmeC
•at specific genomic loci
•Cytosine
•Dnmt•Inhibitors
•(e.g. RG108)
•5-me-Cytosine •5-hme-Cytosine
•Tet2
•Tet2 is involved in the conversion of 5 meC to 5hmeC
•at specific genomic loci
•Cytosine
•Dnmt•Inhibitors
•(e.g. RG108) •Mutations in SMP and AML
•CMML++
•CMML is associated with MS
•Tet2 mutations are frequent and are correlated to aggressive disease
•Mastocytosis Patient Cohort:
•KitD816V increases proliferation of Tet2-deficient BMMCs
0 3 6 10 12 14
•Li
ve C
ell C
ou
nts
(lo
g 10)
•(-/-)
•n=4
•(+/-)
•n=4
•(+/+)
•n=4
•8
•0
•2
•4
•6
•7
•1
•3
•5
•A •B
•The combination of Tet2 loss and c-Kit activation provides factor independent survival of
BMMCs
•Time after IL3 withdrawal (Days)
•0
•C
•Gating on
•GFP +
•Bone marrow derived Tet2-deficient mast cells infected with c-KitD816V have a competitive
growth advantage
CD117
•cKitD816V+ •cKitD816V+ •cKitD816V+
� Confirmed in two independent Tet2-KO models
(lacz and flox)
� Consistent whether infections are done using
« young » or « old » MC cultures (old > 80 days
culture with IL3)
•CD117
•Tet2(+/+)
•GFP
•Tet2(+/-) •Tet2(-/-)
•TET2 MUTATION
•Model of Oncogenic Co-operation
••KITD816V KITD816V
••OTHER MUTATIONSOTHER MUTATIONS••HETEROGENEOUS DISEASE PHENOTYPEHETEROGENEOUS DISEASE PHENOTYPE••AGRESSIVE DISEASEAGRESSIVE DISEASE
•Proliferation
•Differentiation
••HETEROGENEOUS DISEASE PHENOTYPEHETEROGENEOUS DISEASE PHENOTYPE••AGRESSIVE DISEASEAGRESSIVE DISEASE
•Indolent
•Mast cell tumor
•Htert activiy
•C-kit D816V
•Survival
•Immortalization
•Mast cell tumor
• regression•C-kit (WT exon 8,9,11)
•Proliferation
•SCF
•Survival
•No immortalization
•No htert activity
•Telomeres shortening•Mast cell
•progressiopn
•Genetic instability
•Htert expression
AHNMD• Fréquence 30%• Physiopathologie?• Pronostic habituellement mauvais
• Hémopathie myéloïde : SMP, SMD, SMP/SMD– LMMC: précurseur commun?, monocytes D816V, Mutation TET2 30%, évolution
possible vers LAM– LAM : t(8;21) ++, présence SM souvent occulte et péjore le pronostic de la LAM. De
même, présence LAM péjore pronostic de la MS– LMC: pas de BCR-Abl– LMC: pas de BCR-Abl– Hyper-éosinophilie (<20%):
– SHE, leucémie chronique à éosinophiles– FIP1-PDGFRa = imatinib– SM-eo: pas de retentissement habituel cardiaque ou pulmonaire
• Hémopathie lymphoïde: rare. NHL, gammapathie mc
• Si indiqué, traitement dissocié de l’une et l’autre pathologie et traiter l’hémopathie comme si elle était de novo.
• Pas d’effet des HD-CT sur la mastocytose
Mastocytosis Heterogeneity and c-kit
•Tet2
•ASXL1
•CMML
•C-kit 816 V
•negative
•C-kit 816 V
•Other ckit mutations •Other ckit mutations
•other ?
•NHL
•Cytokines (CD40L)
•Tet2
•ASXL1
•C-kit 816 V
•Tet2
•MDS
•CMML
•AML
•Sarcoma
•MCL
•Indolent Masotcytosis
•Agressive mastocytosis
•C-kit 816 V •JAK2,
• FIP1L1-PDGFR,
•Regression
•C-kit 816 V
•Other ?•Pediatric forms
•Other ckit mutations
•WT c-kit
•Adult Forms
•Sarcoma
•MCL
•Other ckit mutations
•WT c-kit
•Others SMP
•Agressive
•Masotcytosis (rare)
•Tet2
•ASXL1
•others
Effect of kinase Inhibitors on Mast cellsand Mastocytosis
C-kit inhibitionC-kit inhibition
STI 571 ?
Effect of STI 571on proliferation of cell lines with juxtamembrane or V814 c-kit mutations
80
100
120
% C
PM
0
20
40
60
0 0.1 1 10
µM
% C
PM
Ba/F3 Kit+IL3
Ba/F3 Kit+SCF
∂27
FMA 3
KIT G559
IC2 V814
P815 (V814)
FMA3 K∆27 KG559 KV814 P815
STI571 (µM) 0 1 10 0 1 10 0 1 10 0 1 10 0 1 10
KWT
.1 1 10
KL - + + - - - - - - - - - - - - - - -
IP anti KIT / Blot anti PY
000
- ++
--
175 kDa
83 kDa
MW
Ct
KIT
Effect of STI 571on wild type, juxtamembrane or V81 4c-kit phosphorylation
IP anti KIT / Blot anti PY
Total cell lysate & Blot anti Grb2
IP anti KIT / Blot anti KIT
--
175 kDa
83 kDa
MW
KIT
Grb226 kDa -
Effects of STI571 on Mastocytosis
• No effect on Mast cells with C-kit mutations within the catalytic domain (D816V)
• In vitro effect on Mast cells without catalytic domain C-kit mutations
c-kit Mutations in Mastocytosis
NH2
cc
cc
cc
Akin et al. Blood. 103:3222, 2004
•Location: Exon 10 (Transmembrane)•Type: Germline•Clinical features:
Childhood onset CMSSM in early 20sWell-differentiated phenotype
COOH
cc
F522C
Well-differentiated phenotype•Functional studies: Gain-of-function•Inhibition by imatinib: Yes (in vitro and clinically)
Therapy with imatinib in a patient with transmembrane c-kit mutation: Proof of concept
150
200
Try
ptas
e (n
g/m
l)
100 mg/d
200 mg/d
300 mg/d
0 25 50 75 100 1250
50
100
Days
Try
ptas
e (n
g/m
l)
300 mg/d
400 mg/d
Akin, Fumo, Yavuz, Lipsky, Neckers, Metcalfe. Blood, 103:3222, 2004
PKC412 (N-benzyl staurosporine)
• Inhibits PKC, VEGFR, Kit, PDGFR, flt3
• Phase I/II trials in hematologic and solid hematologic and solid tumors– Nausea, vomiting,
diarrhea, fatigue
• Inhibits D816V c-kit•Gotlib et al. Blood, in press, 2005
•BAF3 D816V cells
PKC 412
• Agressive mastocytosis
• Mastocytosis associated with C-kit D816V mutation
Signaling of PI-3k/Akt/mTOR•C-KIT
•-•PI •3 kinase
•AKT
•-•m•TOR •RAPAMYCINE
•1•Cyclin D•CDK’s
•G•1 •S
•Cell division
•G•0
•(resting cell)
•+
•P-p70S6k
•Translation/apoptosis
•4EBP/eIF4E
•BMMC
•Lignée BMMC•cellules mastocytaires dérivées de moelle osseuse de souris
•transgéniques pour le c-kit humain
•BMMC
•c-kit wt•BMMC
•c-kit 816
•La mutation D816V du c-kit confère à la cellule BMMC la sensibilité à la Rapamycine
Rapamycin and MS
•Stop
IFN
•CDA
1
•CDA
2
•Start
IFN
•Start Rapamycin
•Masitinib formula: C28H30N6OS
•Molecular weight:
•AB1010 (mesylate salt): 594.76
•Masivet® belongs to the ATP binding pocket molecules kinaseinhibitor 2-amino-4-aryl-thiazole family
•c-Kit •c-Kit
•Proliferation
•AB1010
•Proliferation
Me
N
S
NH
NH
O
N
N
N
Me
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1010,10,050,01
DO
490
nm
AB 1010 (µM)
Inhibition of c-Kit phosphorylation
•AB1010 (mesylate salt): 594.76
•AB1003 (free base): 498.66
•Proliferation •Proliferation
•AB1010
•Anti-c-Kit
•Anti-Phospho Kit Tyr 729
•Anti-Phospho Tyr 4G10
•Masitinib formula: C28H30N6OS
•Molecular weight:
•AB1010 (mesylate salt): 594.76
•Masivet® belongs to the ATP binding pocket molecules kinaseinhibitor 2-amino-4-aryl-thiazole family
•c-Kit •c-Kit
•Proliferation
•AB1010
•Proliferation
Me
N
S
NH
NH
O
N
N
N
Me
0,0
0,2
0,4
0,6
0,8
1,0
1,2
1,4
1010,10,050,01
DO
490
nm
AB 1010 (µM)
Inhibition of c-Kit phosphorylation
•AB1010 (mesylate salt): 594.76
•AB1003 (free base): 498.66
•Proliferation •Proliferation
•AB1010
•Anti-c-Kit
•Anti-Phospho Kit Tyr 729
•Anti-Phospho Tyr 4G10
•Masivet® potently and selectively inhibits c-kit, PDGF receptors, and LynB
••Major target of Major target of MasivetMasivet® (IC® (IC5050 below 1µM)below 1µM)Major targets
(IC50 in nM)
Inhibition of cell proliferation Inhibition of kinase activity
ligandTransfected cells Tumor cell lines
Human c-Kit
WT 150 150 (TF-1) 200 SCF
EC (exon 9) 100 NA NA -
JM (exon 11) 3 50 (HMCI-a155) NA -
TK1 (exon 13) ND 40 (GIST 882) ND -
TK2 (exon 17) 5000 5000 (HMCI) > 10,000 -
Dog c -Kit
Masivet® is a novel, orally administered, protein-t yrosine kinase inhibitor, which potently and selectively inhibits c-kit, PDGF recep tors, and Lyn.
Dog c -Kitd Kit WT 100 NA ND SCF
d Kit EC exon 8 20 NA NA -
d Kit EC exon 9 100 NA NA -
d Kit JM exon 11 5 20 (C2) NA -
Murine c-Kitm Kit WT 150 200 (BMMC) ND SCF
m Kit JM exon11 5 NA NA -
Platelet-derived growth factor (PDGF) receptors
PDGFRα WT 300 - 540 PDGF BB
FIP1L1-PDGFRα - 0.25 (EOL-1) ND -
PDGFRβ 30 ND 800 EGFR-chimera + EGF
Intracellular kinases
LynB NA NA 510 -
Masitinib inhibits Mast cell degranulation and migration
••Human : A model for DogHuman : A model for Dog
••and “vice versa”and “vice versa”
•53
Mast Cell Tumors in Dogs
• Most common cutaneous tumor– 16-21% of all canine
cutaneous tumorscutaneous tumors
• Tissue mast cells in the dermis
• Poor survival <6 months in grade III tumors
D479N
V560G∆∆∆∆418
∆∆∆∆564-576
E860G∆∆∆∆419 (12)
InsFF419
C443YS476I
ITD501-502(2)
D572AD816Y(4)
D816ID816V(353)
Ig1 Ig2 Ig3 Ig4 Ig5
TM JM TK1 TK2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
∆∆∆∆417-418 D419Y
n=603Human mastocytosis
Collaboration : K Hahn Houston USA
Can we compare mastocytosis with dog mast cell tumors ?
Ig1 Ig2 Ig3 Ig4 Ig5
TM JM TK1 TK2
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
Dog mast cell tumor∆∆∆∆826826826826−−−−828- InsDTQ430R
ins 421 aa45
S479I4
N508I
Del/Ins 555-559(5)
ITD571-590(15)
n=88
Team 4 : Cell Signaling, Hematopoiesis and Mechanisms of Oncogenesis
ITD
ITD505-508
K509I(6)
ITD502-503(4)
30% of the dogs are mutated
•Case Report in Mast Cell Tumor.•Case Report in Mast Cell Tumor.
•DAY 0 •DAY 3 •DAY 18
•Case Report in Mast Cell Tumor.•Case Report in Mast Cell Tumor.
•Day •-•40• •Day 0 • •Day 15 • •Day 40••(treatment start) •
0. 25
0. 50
0. 75
1. 00
•EFFICACY of KINAVET on MAST CELL TUMOUR•Pivotal phase III study (n=202)
•Time To Progression – FIRST LINE
ITT population Median TTP (days)
Category n Mb Plc P
All First Line (FL) 85 253 75 0.001
Mutated c-Kit 25 NR 83 0.009
Wild-type c-Kit 53 253 66 0.008
•All First Line
0. 00
0. 25
0. 50
0. 75
1. 00
Ti me t o progressi on (days)
0 100 200 300 400 500 600
STRATA: group=AB1010 Censored group=AB1010 group=Pl acebo
0. 00
0. 25
0. 50
0. 75
1. 00
Ti me t o progressi on (days)
0 100 200 300 400 500
STRATA: group=AB1010 Censored group=AB1010group=Pl acebo Censored group=Pl acebo
0. 00
Ti me t o progressi on (days)
0 100 200 300 400 500 600
STRATA: group=AB1010 Censored group=AB1010group=Pl acebo Censored group=Pl acebo
Wild-type c-Kit 53 253 66 0.008
•Mutated c-kit •Wild-type c-kit
•Mb, masitinib; Plc, placebo; NR, not reached
Case Report of Agressive MC
• Female 67y past history of Flushes, Diarrhea, abdominal pain, syncopes.
– Hb 10,6, Plt 124000, wbc 8100; 4600 PNN, 7 % circulating mastocytosis
– Bone marrow aspiration 77% pathologic mast cells – Bone marrow aspiration 77% pathologic mast cells
– Bone marrow biopsy : 90 % infiltration
– Tryptase sérique 351 µg/L (N<15)
– Histamine sérique 14314 nmol/L (N<15)
– Caryotype: normal (46XX)
– Flow cytometry: 40% Ckit+, 12% CD25+, 2%
Biological findings
•Deletion 501-502
•Blood •Bone Marrow
In vitro effect of MasitinibPostive C
ontorol
Cos t
ransfected
Cos t
ransfected +masitinib
Cos t
ransfected+masitinib
1
•Cos
•Postive C
ontorol
•Cos t
ransfected
•Cos t
ransfected +masitinib
0.1
•Cos t
ransfected+masitinib
1
•Deletion 501-502