4a. Tirosin Chinasi e MPD
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Transcript of 4a. Tirosin Chinasi e MPD
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WHO Integrated Classifications
Morphology:Cytology
Histopathology
Molecular GeneticsCytogenetics
Immunology:Immuno-cyto-histochemistry
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HEMATOPOIESIS HEMATOPOIESIS
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morfologiaPB
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cariotipo
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BCR/ABL1
ABL1/9q34BCR/22q11
Ph
t(9;22)(q34;q11)
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BCR
ABL1 Ph-Ph+
NORMAL nuclei BCR/ABL1-positive nuclei
t(9;22) (q34;q11)
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Indagini che identificano le cellulecon cromosoma Filadelfia
Metodica Potere di risoluzione
Citogenetica Convenzionale 1x102
FISH (Ibridazione in Situ con Fluorescenza) 1x103
RT-PCR 1x104 (105)
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Diverse breakpoints/diverse fusion proteins
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PCR analysis of BCR/ABL1 transcripts
- P190 transcript: Acute lymphoblastic leukemia (ALL)
- P210 transcript: chronic myeloid leukemia (CML)
- P230 transcript: chronic neutrophilic leukemia (CNL)
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The ABL1 gene
•homologous to v-abl
•IN G1 it is bound by Rb1
•Knock-out mice are leukopenic
•when overexpressed --> cell cycle arrest
NLSACTIN
BINDINGSH1SH2SH3
DNA BINDING COOHNH2
ATPbind
NLS: Nuclear Localisation SignalTyr Kinase
ABL protein
Proteininteraction
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The BCR gene
•Ubiquitous expression
•cytoplasmic, but pericromosomic during mitosis
•Knock-out have nearly normal hematopoiesis
PHSer/Trhkinase
DD DBL/GAP COOHNH2 177Y
Sh2 binding
BCR protein
Dimerization domain
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Principali effetti di Bcr-Abl nel progenitore emopoietico
NUCLEO
Bcr-Abl 1. Stimolo alla proliferazione
4. Diminuzione della funzione di ABL a livello nucleare: instabilità genomica
Paxillin
F-actin
2. Diminuzione dell’adesione allo stroma emopoietico
Abl
3. Ridotta morte apoptotica
Ciclo cellulare
RAS
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CITOPLASMA
NUCLEO
ABLTirosin Chinasi
TIROSIN CHINASI E NEOPLASIE MIELOIDI
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Glivec (imatinib mesilato) Inibitore selettivo della tirosina-chinasi Bcr-Abl
La target therapy della LMC
Un approccio rivoluzionario
in terapia oncologica (target therapy): per la prima volta un farmaco che
riconosce ed elimina solo le cellule portatrici dell’anomalia
molecolare
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TERAPIE MOLECOLARI(MIRATE/BERSAGLIO/TARGET/INTELLIGENTI)
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TERAPIE MOLECOLARI(MIRATE/BERSAGLIO/TARGET/INTELLIGENTI)
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BCR/ABL1 + loss 5'ABL1/3'BCR
normal BCR/ABL1
BCR/ABL1 + loss 5'ABL1
der(9)
Karyotype D-FISH
0
10
20
30
40
50
60
70
80
1 2 3 4 5 6 7
Serie1
0 1 2 4 8 12 17 months
FISH monitoring
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IMATINIB: RESISTENZE
• Mutazioni nel dominio di tirosin-chinasi
• Amplificazione di BCR-ABL1
• Nuove abberrazioni cromosomiche
• alterato metabolismo dell’imatinib
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Inibitori Tirosin chinasi
• Imatinib
• Nilotinib
• Dasatinib
• Sumitinib
• …………
• …………
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Progressione della Leucemia Mieloide Cronica
N
NN
N
N
N
N
N
N
N
N
N
N
N
NN
N
N
N
N
N
N
N
NN
N
N
NN
NN
N N
N
NN
N
N
NN
N
N
N
N
NN
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NN
N
N
NN
N
Ph+
Ph+
Ph+
Ph+
Ph+
Ph+
Ph+ Ph+
Ph+Ph+
Ph+
Ph+
Ph+
Ph+Ph+
Ph+
Ph+Ph+
Ph+Ph+
Ph+
Ph+
Ph+
Ph+ Ph+
Ph+Ph+
Ph+
Ph+
Ph+ Ph+
Ph+Ph+
Ph+ Ph+ Ph+ Ph+ Ph+ Ph+
Ph+
Ph+Ph+
Ph+
Ph+
Ph+
Ph+
Ph+Ph+
Ph+
Ph+
Ph+
Ph+
Ph+
Ph+Ph+
Ph+
Ph+
Ph+Ph+
Ph+
Ph+
Ph+Ph+
Ph+Ph+
Ph+
Ph+
Ph+
Ph+
Ph+
Clone indifferenziato,crisi blastica
N = cellule normali
1 2 3 4 5
Adattata da Saglio G, Congresso SIE, Firenze 2001
Midollo osseo
Compartimento staminale
Anno
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Chronic myelogenous leukemia
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CMLBCR/ABL1
Others
PV
MFET
Myeloproliferative Disorders
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HEMATOPOIESIS HEMATOPOIESIS
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TYROSINE KINASE RECEPTOR FAMILY
Tyr Kinase domains
Cell Membrane
Extra Cellular
Intra Cellular
Phosphorilation - Dimerisation - Signal Transduction ( RAS; STAT; MAPK…)
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RECEPTOR FAMILY
Tyr Kinase domains
Cell Membrane
Extra Cellular
Intra Cellular
Phosphorilation - Dimerisation - Signal Transduction ( RAS; STAT; MAPK…)
JAK 2MPL
ARG (ABL2) FLT3KIT
PDGFRαPDGFRβFGFR1
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CITOPLASMA
NUCLEO
. ABL1
. JAK2 Tirosin-chinasi citoplasmatica
. PDGFRB
. PDGFRA
. FGFR1
. C-KITRecettori(Tirosin Chinasi)
TIROSIN-CHINASI E NEOPLASIE MIELOIDI CRONICHE
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ST
AT
ST
AT
ST
AT
JAK
JAK-STAT PATHWAYJAK-STAT PATHWAY
NucleusNucleusCytosolCytosol STATSTAT
Plasma membranePlasma membrane
JAKJAK
ST
AT P P
P P
JAKJAKS
TA
T
ST
AT
ST
AT
ST
AT
ST
AT P
ST
AT
P
EPOEPO
EPOEPO
EPOEPO
EPOEPO
P
P
P
P
Ep
o-R
Ep
o-R
Ep
o-R
Ep
o-R
Ep
o-R
Ep
o-R
JAK
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JAK-STAT PATHWAYJAK-STAT PATHWAY
NucleusNucleusCytosolCytosol STATSTAT
Plasma membranePlasma membrane
JAK-Val617FJAK-Val617F
ST
AT
ST
AT
ST
AT
ST
AT
ST
AT P
ST
AT
P
P
P
P
Ep
o-R
Ep
o-R
ST
AT
ST
AT
ST
AT
ST
AT P P
P P
Ep
o-R
Ep
o-R
JAK-Val617FJAK-Val617F
JAK-Val617FJAK-Val617F JAK-Val617FJAK-Val617F
P
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JAK2 V617F
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MUTAZIONI DI JAK2(Activating point V617F mutation)
Esone 14 JAK2:
G sostituita da una T (nucleotide 1849)
Valina sostituita da Fenilalanina (aminoacido 617)
Mutazione somatica: cellula staminale pluripotente eterozigote o omozigote attivazione costitutiva di
JAK2
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MPL somatic mutation in CMPD
W: triptofanoL: leucinaK: lisina
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C-MPL mutations: TGG TTG conversion in MPLW515L
TGG AAG conversion in MPLW515K
transmembrane domain mut
C-MPL mutations may occur with JAK2V617F
Frequency: 5-10%
Diseases: PMF and ET
CMPD
W: triptofanoL: leucinaK: lisina
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CMLBCR/ABL1
Others
PV
MFET
Myeloproliferative Disorders
JAK2 MPL
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CITOPLASMA
NUCLEO
Recettore(Tirosin Chinasi)
TIROSIN CHINASI E NEOPLASIE MIELOIDI
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CMLBCR/ABL1
Others
PV
MFET
Myeloproliferative Disorders
JAK2 MPL
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Proliferation
RAS
GRB-2
SOS
PDGFRLigand PDGFR HLH
PDGFRα 4q12PDGFRβ 5q33
Tyrosin kinase domain
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MPD Ph negative (eosinophilia; monocytosis)
t(5;12)(q33;p13)
PDGFR gene
HLH DNA-bindingN C
ETV6 gene
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t(5;12)(q33;p13)-ETV6/PDGFR
Diagnosi: Ph- CML CMML MDS
Eosinofilia BM/PB
Monocitosi PB>8%
Risposta al trattamento con Imatinib Mesilato
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7q11/HIP1
14q22/NIN
14q32/KIAA1509
1p36?
17p11/HCMOGT-1
12p13/ETV6
17p13/RABEP1
14q32/CEV14
10q22/H4
16p13/?15q22/TP53BP1(RABPT5)
12q13/?
2q37/?
3p21/?
1q23/PDE4DIP
1q21/?????
PDGFRB
Geni partners di PDGFRB nei disordini Mieloproliferativi cronici Ph-
NH2 COOH
PDGFRBGene Partner
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UN GENERICOMBINAZIONI
GENOMICHEMULTIPLE
UNA MALATTIA
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Proliferation
RAS
GRB-2
SOS
PDGFRLigand PDGFR HLH
PDGFRα 4q12PDGFRβ 5q33
Tyrosin kinase domain
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Reattiva non clonale
EOSINOFILIA
Sindrome ipereosinofila idiopatica / leucemia eosinofila cronica: HES/CEL
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REATTIVA NON CLONALE
INFEZIONI E PARASSITOSI
MALATTIE ALLERGICHE
MALATTIE DEL CONNETTIVO E AUTOIMMUNI
PROCESSI NEOPLASTICI
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1. conta degli eosinofili nel sangue persistentemente
superiore a 1,5 x109/l per un periodo superiore a sei
mesi
2. segni e/o sintomi di coinvolgimento di organi
3. assenza di una causa nota o di un’anomalia clonale
HES
I 3 criteri di definizione della HES in base alla WHO sono:
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RP11-3H20
FIP1L1 CHIC2 PDGFRA
telcen
telcenFIP1L1/PDGFRA
Hypereosinophilic Syndrome, Myeloproliferative Variant
4q12
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I-FISH 34 pts with HES
FIP1L1/PDGFR+ FIP1L1/PDGFR-
PTS 8 26
M/F 7/1 12/14
Median age 42 51
Hepatomegaly 6 5
Splenomagaly 6 6
Hearth 2 3
CNS 2 3
Lung 1 3
Skin 4 10
Response toSTI571
7/7 0/4
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WHO Classification of Systemic Mastocytosis
Mast cell leukemia
Aggressive systemic mastocytosis
SM with an associated Haematopoietic clonal non-mast cell lineage disease
Indolent Systemic Mastocytosis ( Isolated bone marrow mastocytosis;
Smouldering systemic mastocytosis )
Variants and subvariants
FIP1L1 PDGFRACHIC2(Deletion)
KIT(Mutations)
5’ 3’ 3’5’centromero telomero
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C-Kit activation loop: D816V (aspartic acid to valine at aa 816)
D816Y (aspartic acid to tyrosine at aa 816)
Resistence: imatinib mesilate (in vitro and in vivo)
Sensitivity: PK412 (in vitro)
C-KIT mutations
Systemic mast cell disease / acute myeloid leukemia
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CITOPLASMA
NUCLEO
Recettore(Tirosin Chinasi)
PDGFRBPDGFRAFGFR1KIT
TIROSIN CHINASI E NEOPLASIE MIELOIDI
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47,XX,t(8;13)(p11.2;q12q13),+21
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der(13)
der(8)813
t(8;13)(p11;q12)-ZNF198/FGFR1
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8p11
centromere telomereFGFR1
RP11-350N15
5’ 3’
t(6;8)(q27;p11)/FOP-FGFR1: MPD/NHL(Popovici C et al., Blood 1999)
t(8;9)(p11;q33)/CEP110/FGFR1: MPD/NHL (Guash G et al, Blood 2000)
ins(12;8)(p11;p11p22)/FGFR1OP2-FGFR1: MPD/NHL (Grand EK et al., GCC 2004)
t(8;13)(p11;q12)/ZNF198-FGFR1: MPD/NHL (Reiter A et al., Blood 1998)
t(8;19)(p11;q13)/HERVK-FGFR1: MPD/NHL (Guash G et al., Blood 2003)
t(8;22)(p11;q11)/BCR-FGFR1: CML (Demiroglu A et al., Blood 2001)
t(7;8)(q32;p11)/TRIM24-FGFR1 (Belloni E et al., Genes Chrom Cancer 2005)
t(8;17)(p11;q11)/MYO18A-FGFR1 (Belloni E et al., Genes Chrom Cancer 2005)
t(8;9)(p22;p24)/PCM1-JAK2 (Adelaide J et al., Leukemia2006)
Rearrangements with eosinophilia
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fusion partners
FGFR1 13q12/ZNF198
9q34/CEP110 12p11/FGFG1OP2
22q11/BCR
Ig1 Ig1 transmembraneN CIg1 Ig2 Ig3 TM TK1 TK2
Ig-like domainstransmembrane
tyrosin kinase
19q13/HERV-K
6q26/FOP
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CITOPLASMA
NUCLEO
ABL ; JAK2 Tirosin Chinasi
Recettore(Tirosin Chinasi)
PDGFRBPDGFRAFGFR1KIT
TIROSIN CHINASI E NEOPLASIE MIELOIDI
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1. Chronic myeloproliferative diseases
- Chronic myelogenous leukemia
- Chronic neutrophilic leukemia
- CEL/ hypereosinophilic syndromePDGFRA
- Polycythemia vera JAK2
- Chronic idiopathic myelofibrosis JAK2
- Essential thrombocythemia JAK2
-Chronic myeloproliferative disease, unclassifiable PDGFRB
-Systemic Mastocytosis KIT
Ph+
Ph-
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L’IMATINIB MESILATO PUO’ ESSERE UNA VALIDA
TERAPIA NEL TRATTAMENTO DEL DANNO D’ORGANO
In 1 paziente con lesioni del SNC dopo undici mesi di terapia
si verificava una riduzione delle lesioni encefaliche
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Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F
Mutation
EPO-dependent signal EPO-independent signal
EPO, TPO, G-CSF, GM-CSF, IL3, IL5: cytokines using JAK2 for signaling transduction
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Acquired PDGFRA mutations with resistance to imatinib
Kinase domain (ATP- binding region)
T674I (treonine to isoleucine at aa 674)
Resistence to imatinib therapy
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RP11-110K18(5’ZNF198) +RP11-350N15 (FGFR1)
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The 8p12 myeloproliferative syndrome8p12 MPS
Myeloid hyperplasia
Eosinophilia /Monocytosis
Associated T (B)-cell lymphoma
Progression toward AML
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centromere telomereCSF1R PDGFRB CDX1
5q33
cosmid 9-4 cosmid 4-1
5’3’
t(1;5)(q23;q33)/PDE4DIP- PDGFR: MDS/MPD (Wilkinson K et al., Blood 2003)
t(5;7)(q33;q11)/HIP1-PDGFR: CMML (Ross TS et al., Blood 1998)
t(5;10)(q33;q22)/ H4-PDGFR: aCML (Schwaller J et al., Blood 2002)
t(5;12)(q33;p13)/ETV6/-PDGFR: aCML, CMML, RAEB (Golub R et al., Cell 1994)
t(5;14)(q33;q24)/NIN- PDGFR: MPD (Vizmanos JL, et al., Cancer Res 2004)
t(5;14)(q33;q32)/CEV14- PDGFR: AML (Abe A et al., Blood 1997)
t(5;17)(q33;p13)/RABAPTIN-5- PDGFR: CMML (Magnusson MK et al., Blood 2001)
Rearrangements with eosinophilia
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Loss of heterozygosity of chromosome 9 – occurs commonly in P vera
normal LOH
p24 JAK2
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Characteristics of bcr-abl
•Only cytoplasmic
•permanently activated
•several targets
•it mimics some TK receptors, inducing constitutive activation of several pathways
•bypass of regulatory mechanisms