Molecular Aspect of CML 2014 PPTok

8/17/2019 Molecular Aspect of CML 2014 PPTok

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dr. Irza Wahid, SpPD-KHOM

Curriculum Vitae :T.TGL-L : Padang, 23 November 19!

"abatan #e$arang :

- %e&ala #ubbagian 'ematologi

(n$ologi )edi$ *ag. +P % nand


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MOLECULAR ASPECT OF PATHOGENESISAND MANAGEMENT OF

CHRONIC MYELOID LEUKEMIA

IRZA WAHID

SUBDIVISION OF HEMATOLO! " MEDI#AL ON#OLO!,DEPARTEMENT OF INTERNAL MEDI#INE

ENERAL HOSPITAL OF M D$AMILFA#ULT! OF MEDI#INE, ANDALAS UNIVERSIT!, PADAN


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INTRODUCTION

L%&'a%(ia a))*&+ *r /01 * a22 )a+)%r i+ h&(a+3-0

4 I+)id%+)%5 6-37 )a% p%r 377,777 p*p&2ai*+ #ML a))*&+ *r 361-871 * a22 ad&2 2%&'a%(ia9,6

4 I+)id%+)%5 3-8 )a% p%r 377,777 p*p&2ai*+9,:

4 O))&r 2i;h2< (*r% r%=&%+2< i+ (%+ ha+ >*(%+ ?3.9-8.853@

M%dia+ pai%+ a;% a dia;+*i5 66-:7 +

* % )a&%d < a+ &+d%r2>-d%p.iar).r. 8. #a+)%r R%%ar)h UK. AGai2a2% a5

hp5>>>.)a+)%rr%%ar)h&'.*r;a*&)a+)%raii)i+)id%+)%. 0. F%r2a< $ % a2. EU#AN. AGai2a2% a5 hp5>>>-

d%p.iar).r%&)a+%&)a+.h(. 9. Dr&'%r B$. Cancer Cell . 87783503-0:. 6. r%%+2%% RT % a2. CA Cancer J Clin. 877363536-0:. :.

Ri% LA % a2. SEER #a+)%r Saii) R%Gi%>, 3C6-8773. AGai2a2% a5 hp5%%r.)a+)%r.;*G)r3C6J8773. . #*r% $.

Hematol Oncol Clin North Am. 8779356:C-69. . N*>%22 P# % a2. J Natl Cancer Inst. 3C:3853730-3706.

MOLECUL

ASPECT


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CA Cancer J Clin 2011;61:212-236. VC 2011 American Cancer Scie!".


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S!r#$!#r Sel


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%rmal &ar"!"'e


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(a)e Pem*ela+an Sel


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DNA -------------> RNA ------------> PROTEIN


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Haematopoiesis: !oo" Ce!! Li#ea$es

Dia;ra( r%pr*d&)%d >ih p%r(ii*+ r*( W.H.

Fr%%(a+ #*(pa+ !*r', N!, USA.

H*ra+d AV % a2. Essential Hematology. 9h %d.

O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.

Haematopoiesis: p%o&ess '()*i&* '!oo"-&e!! !i#ea$es a%e

p%o"+&e" '( 'o#e ma%%o)

,Cs )*ite '!oo" &e!!s. o%

!e+/o&(tes0 s+'"i1i"e" i#to " M(e!oi" !i#ea$es " L(mp*oi" !i#ea$es

G%a#+!o&(tes massi1e!( e2pa#"e"

i# CML


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Stem Ce!!s a#" Haematopoieti& Di33e%e#tiatio#

Dia;ra( r%pr*d&)%d >ih p%r(ii*+ r*( Pr*. Dr. A)hi( L%&z, Ma D%2r)' #%+%r *r M*2%)&2ar M%di)i+%, B%r2i+.

H*ra+d AV % a2. Essential Hematology. 9h %d. O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.

Haematopoieti& stem &e!!sHaematopoieti& stem &e!!s&apa'!e o3 &apa'!e o3

" Se!3-%e#e)a!Se!3-%e#e)a!

" Di33e%e#tiatio#Di33e%e#tiatio#

Di33e%e#tiatio# a#" p%o!i3e%atio#Di33e%e#tiatio# a#" p%o!i3e%atio#

&o#t%o!!e" '( mo!e&+!a% si$#a!s&o#t%o!!e" '( mo!e&+!a% si$#a!s " Co#ta&t )it* st%oma! &e!!s i#Co#ta&t )it* st%oma! &e!!s i#

'o#e ma%%o)'o#e ma%%o)

" G%o)t* 3a&to%sG%o)t* 3a&to%s


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Si$#a! T%a#s"+&tio#

Ad%i AA % a2. J Clin Oncol. 877680560:-6970. R%pr*d&)%d >ih p%r(ii*+.

Prli,era)i

i,eren)ia

A''!)i)


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Pat*o$e#esis


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Ge#eti&s a#" Ce!!+!a% P%o!i3e%atio#

N%*p2ai) ra+*r(ai*+i+iia%d <

4 P*i+ (&ai*+

4 #hr*(**(a2 2*,

d&p2i)ai*+, *r

i+appr*pria%

r%)*(i+ai*+4 L* * %pr%i*+ * a

;%+% ha i+hii )%22

pr*2i%rai*+ *r pr*(*%

ap*p*i

Dia;ra( )*&r%< * Nai*+a2 #a+)%r I+i&%, USA.

H*ra+d AV % a2. Essential Hematology. 9h %d. O*rd, UK5 B2a)'>%22 S)i%+)% 87735396-3:3.


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#ML4 Pr*2i%raiG% di*rd%r * h%(a*p*i%i) %( )%22

Phi2ad%2phia ?Ph@ )hr*(**(%

4 U+i=&% )hr*(**(a2 a+*r(a2i<

B#R-ABL


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4 5 6 7 8

9 ; < 4= 44 45

46 47 48 49 4 4;

4< 5= 54 55 Y

P* C*%omosomeCytogenetic Abnormality of CML


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?C88@?=09=33@4 ra+2*)ai*+4 = 2*+; ar( * )hr*(**(%

P* C*%omosomeReciprocal Translocation

I(a;% r*(5

Ka2ida M, Ka+aria+ H, Ta2paz M. JAMA. 87738:?@5C6-C


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CR ? AL O#&op%otei#

4Ph )hr*(**(% >a di)*G%r%d i+ 3C:7 < H&+;%r*rd a+d N*>%22.

4T* % h% r%&2 * )hr*(**(a2 ra+2*)ai*+ ?R*>2%a< ;r*>h, &rGiGa2, ra+*r(ai*+

4B< MAPK, $NK, SAPK, NF-', STAT, SR#, a(i2< 'i+a%


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P* C*%omosome

P%e1a!e#&e o3t*e P*i!a"e!p*ia &*%omosome

T(pe o3 !e+/emia P*@ patie#ts 0

CML


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P* C*%omosomebcr-abl Fusion Gene

I(a;% r*(5

Ka2ida M, Ka+aria+ H, Ta2paz M. JAMA. 87738:?@5C6-C


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CR-AL P%otei#Disrupts Signal Transduction Pat!ays

Prolonged survival

Increased migration from

bone marrow

Uncontrolledproliferation


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ian)i)


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Pe%ip*e%a! !oo" Smea%

No%ma! C*%o#i& p*ase CML

I#&%ease" ,Cs

Mat+%e

Immat+%e

Note:

I#&%ease" 'asop*i!i&

$%a#+!o&(tes 'asop*i!

i# pa%ti&+!a%


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C!i#i&a! Co+%sePases of "ntreated CML

Disease p%o$%essio#

C*%o#i& p*ase

7?9 (ea%s

B;8 o3 patie#ts

p%ese#t i# t*is

p*ase

48 ma%%o) o%

pe%ip*e%a! '!asts

Up to 4 (ea%

,ei$*t !oss. 3e1e%.

'o#e pai#

48?5= ma%%o) o%

pe%ip*e%a! '!asts

A 3e) )ee/s to 9

mo#t*s

Poo% p%o$#osis %api"!(

3ata!

> 5= ma%%o) o%

pe%ip*e%a! '!asts

A&&e!e%ate" p*ase !ast &%isis


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C!i#i&a! C%ite%ia a#" P*ases o3 P*@ CML

Pa%amete% C*%o#i&p*ase A&&e!e%ate" p*ase !ast &%isis

,C &o+#t 5= 2 4=< &e!!sL

!asts 48 48?6= 5=?6=

asop*i!s 5= 5=

P!ate!ets o% #o%ma! o%

Ma%%o) &e!!+!a%it(

C(to$e#eti&s P*@ P*@ P*@

bcr-abl @ @ @

WB# >hi% 2**d )%22

PhQ Ph )hr*(**(%"p*iiG%

C(to$e#eti&


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C(to$e#eti&Fluorescence #n Situ $ybridi%ation &F#S$'

Courtesy of Charles L. Sawyers, M, !CLA.

M%h*d *r d%%)i+; "cr#a"l *+ h% Ph )hr*(**(%

bcr-abl

La'e!e" bcr-abl $e#e

La'e!e" DNA p%o'e

3!+o%es&e#t0

bcr-abl $e#e

Sepa%ate DNA st%a#"s

a#" a"" !a'e!e" p%o'e

N+&!ea% DNA

M ! !


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Mo!e&+!a%Polymerase Cain Reaction

RT-P#R d%%) "cr#a"l ra+)rip

R-P#R =&a+ii% "cr#a"l ra+)rip

4 B% i+d% * (i+i(a2 r%id&a2 di%a% ?MRD@4 R%p*ri+; Gari% %>%%+ 2a*ra*ri%

4 Sa+dardiz%d I+%r+ai*+a2 S)a2% ?IS@ i+

d%G%2*p(%+


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T+era'"


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Hemato!o$i&%espo#se

C(to$e#eti&%espo#se

Mo!e&+!a%%espo#se

Comp!ete '!oo"&o+#ts CCs0

Ka%(ot(pi#$ Re1e%se t%a#s&%iptasepo!(me%ase &*ai# %ea&tio#RT-PCR0

F!+o%es&e#t i# sit+*('%i"iJatio# FISH0

Rea!-time +a#titati1epo!(me%ase &*ai# %ea&tio# R-PCR0

%rmal A*)ence A*)ence

Mo#ito%i#$ T*e%ape+ti& Respo#se


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'&%-a'! M+tatio#a! A#a!(sis

M&ai*+ i+ h% 'i+a% d*(ai+ ?KD@ * "cr#a"l (a< % a*)ia%d >ih

r%ia+)% * 2iG%)

4 Pai%+ >ih di%a% pr*;r%i*+ *+ 2iG%) >h* haG% p**r

)h* haG%

i;+ii)a+ i+)r%a% i+ h% "cr#a"l 2%G%2, h*&2d % ar;%%d *r

(&ai*+ &di%

4 M&ai*+ d%%)%d i+ *G%r C7 di%r%+ p*ii*+ i+ "cr#a"l

4 T036I (&ai*+ a*)ia%d >ih p**r pr*;+*i


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D%+$ Resista#&e


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S+mma%( a#" Co#&!+sio#s

M*2%)&2ar ap%) i G%r< i(p*ra+ i+ pah*;%+%i, dia;+*i a+d h%rap< * #

Ph )hr*(**(% a+d &i*+ * B#R-ABL ;%+% a a ai) (%)ha+i( * #ML

4 Tra+2*)ai*+ * 8 %;(%+ " ?C88@ " r%&2i+; i+ a+ a+*r(a2 h


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Molecular Aspect of CML 2014 PPTok