MAJAlAH KEDOKTERAN NUSANTARA
.
.
MAJALAH KEDOKTERAN NUSANTARA
THE JOURNAL OF
MEDICAL SCHOOL UNIVERSITAS SUMATERA UTARA PEMBINA
Rektor Universitas Sumatera Utara PENANGGUNG JAWAB
Dekan Fokultas Kedokteran USU
:
WAKIL PENANGGUNG JAWAB
Pembantu Dekon III Fokultas Kedokteran USU PEMIMPIN REDAKSI
Prof. dr. H. Munar Iubis, SpA (K) WAKIL PEMIMPIN REDAKSI
dr. Isti IImiati Fujioti, Msc REDAKSIPELAKSANA
Prof. Dr. dr. Iskandar Jcpordi, Sp.BS • dr. Ibnu Alferaly, Sp. PA • dr. Selfi Nafioti, Sp.A
dr. Teti Amon Nasution, M.Med.Sc • dr.Muhammad Rusdo Harahap, Sp. OG
Dr. Ir Erno Mutioro, M.Si
REDAKSI AHLI
Prof. dr. H. Chairuddin P. lubis, DTM&H, SpA(K) • Prof. dr. R.M. Potmosontjojo, Sp.BS (FK-UI)
Praf. dr. Darwin Dolimunthe, phD • Prof. dr. Dr. Irma D.Roesyonto, Sp. KK (K) • Prof. dr. Darulkutni Nosution, Sp.S(K)
Prof. dr. Adikoesoema Amon, Sp.PK{KH) • Prof. dr. Abdul Rosyid, Sp.R, ph.D. profdr.Abdul Rachmon Soragih, Sp.THT(K)
Prof. dr. Chairil Anwar, DAP&E, PhD lFK UNSRI) • dr. Foisal Yatin, DTM&H, MPH (Litbong Kes RI] • Dr. Dato Zainuddin Wazir (Malaysia)
SEKRETARIS REDAKSIIDISTRIBUSI
Sri Hartaty, S.Sos
Dewi Sri Hondayoni, SE
BENDAHARA
Berliano Hutasuhut, SE ALAMAT REDAKSI
Fokultos Kedokteron
Universitas Sumotera Utora
Jolon dr. T. Mansjoer No.5 Medon 20155
Telepon +62-61-821 1045 Fox +62-61-821 6284
Email:
[email protected]
IZIN TERBIT
SK Menteri Penerangon Republik I do esio
No. 256/SK/Ditjen PPG/ STT/ 1976
ISSN 0216-325X
DICETAK OLEH
.' 2.
,
10
k
an 101
Susunan Redaksi Kata Pengantar Petunjuk untuk Penulis Daftar lsi
Daftar lsi i
ii
iv
vi
1)f,
Tinjauan Pustaka bel I.
P ar Cji Cungkit Kulit Pada Deteksi ATOPI Rudy. Rita Evalina; Lily Irsa, M.Sjabaroeddin Loebis Pectalaksanaan Nyeri Pada Pasien Pediatri
411
Hasanul
417
~-ek5 i l' O .
!54 a
CI
virus epstein barr sebagai penyebabkarsinorna
Rusdiana
Timpanosklerosis I Siti Hajar H. Ir terpol D\ I : SebuahProsedur Penangangan korbanmeninggalpd bencanamassal
Reinhard Jhon Devison, Rita Mawarni, H. Mistar Ritonga &-~. • Radiografi Dada Pada Tuberkolosis Pam
R i .lfahruzar Lubis :k;-.- ' pada Skizofrenia
425
431
436
441
,'.[ sta/ a. .lf Amin
446
..!...o;"Ck Mecikolesal visum et epertum tumpul pd kepaIa Reinhard Jhon Devison, H. Mistar Ritonga, H. Guntur Bumi Nasution ? e ; . atan DeltriumPasca KontusioSerebri
454
.'- fusIa/ a. .If Amin
461
· . - ~- Pasien PsikiatriAnak & Remajadi lnstalasi Rawat Jalan di RSUD, Pringadi J ita Saragih . , ! , : ~ . lar Basis of Acute Promyelocytic Leukemia
469
Z ulh am
475
· est ess Legs Syndrome Kiki .If Iqbal,A.ldy S. Rambe, Darulkutni Nasution
479
stipasi Fungsionalpada Bayi & Anak Supriatmo
486
licol
Terapi Medikamentosa Untuk Menguraogi SpastisitasPada Anak Penderita Palsi Serebral Zulkarnain, Johannes Saing, YazidDimyati
493
!Ium
Laporan Kasus
n
an
c 9
cdo orrn
ed I.
an
;(0
r ary Ewing's Sarcoma Rr. Sury Indhaty
498
~.:.::
rmoida Renal Cell Carcinoma J. -~. Chrestella, Gani JY. Tambunan, Delyuzar
idck tulis
502
· • . ~ ar; dingan
.·L "
validitas antara siriraj stroke score, allen score dan algoritrna gajah mada untuk diagnosa kini pasien stroke akut suri Kadri 508
·- ..-- : ensia Pigmenti
P .... Irma D Roesyanto-Mahadi, Chairiyab Tanjung
513
\, _.::. te Brain Abscesses in a Newborn baby: Case Report
Rina A.r. Saragih, Munar Lubis
518
::-':'.:0 entorial Meningioma
Rr. Su.:yI
523
-:
TINJAUAN PUSTAKA
r OD ..... :
~
husett s luences j sorder ~
.
Molecular Basis of Acute Promyelocytic Leukemia
Am.
dr. Zulham, M.Biomed. 1 and Prof. dr. Jeanne Adiwinata Pawitan, MS, PhD 2
a ctivity ?ectruID isme-L
Department, Faculty of Medicine, University of Sumatera Utara, Medan, Indonesia.
)isorder.
:3 103 .ht
'v a s iv e . Loosen gn osis & . teGraw-
ABSTRACT: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia . haracterized by accumulation of abnormal promyelocytes in the bone marrow. The outcome of APL treatmet - s been improved dramatically so that APL is regarded as curable. APL exhibits fusion of one allele of the rerinoic acid receptor-alpha gene (RAR) on the chromosome 17q21 with one of the partner (X) genes: PML, LZF, NPM, NuMA, and STAT 5b. The strategy for the management of APL is the induction of the .:.·ffe,rentiation, apoptotic induction of cells with incomplete cytodifferentiation, and inhibition of histone : eacetylases (HDACs) activity. Keywords: histone deacetylase, leukemia, promyelocytes, retinoic acid receptor, transclocation -illSTRAK: Acute promyelocytic leukemia (APL) adalah suatu subtipe acute myeloid leukemia yang berbeda
. engan ciri akumulasi promyelosit abnormal pada sumsum tulang. Hasil pengobatan APL telah meningkat secara dramatis sehingga APL dapat dikatakan sebagai penyakit yang dapat disembuhkan. APL menunjukkan -_si satu aiel gena retinoic acid receptor-alpha (RAR) pada kromosom 17q21 dengan salah satu gen partner: \11-, PLZF , NPM, NuMA, dan STAT 5b. Strategi penatalaksanaan APL adalah induksi differensiasi, induksi · ptosis terhadap sel dengan sitodifferensiasi yang tidak sempurna, dan menghambat aktivitas Histone zeacetylase (HDAC). ·ata kunci: histone deasetilase, leukemia, promyelosit, retinoic acid receptor, translokasi
',""TRODUCTION - cute promyelocytic leukemia CAPL) is a distinct _' type of acute myeloid leukemia. The accumulation .:abnormal promyelocytes in the bone marrow is a · sracter of APL. This disease represents 10 to 15 cents of the cases of acute myeloid leukemia in Its and affects approximately 3000 individuals . _.' year in the US alone. The outcome of treatment of APL has been roved dramatically so that APL is regarded as .:.Jle. This achievement is resulted from the ances in the molecular basis and therapeutic ~tegie s of APL. However, some patients of this sease are not curable. Therefore, combination of morphologic, _-:ogenetic, and molecular analyses is important for · .irnal management of APL patients and better erstanding of the pathogenesis of APL. This . i ew discusses the basis in the molecular and z::
etic ofAPL pathogenesis.
RAR Translocation as the Basis of APL Pathogenesis Acute promyelocytic leukemia exhibits fusion of I allele of the RAR on the chromosome 17q21 with one of the partner (J) genes. The fusion genes are generated from either reciprocal translocation or interstitial deletion. The partner genes, summarized in table, are structurally diverse. Translocation between PML and RAR was involved in most cases of APL (Figure 1).'
Table. Partner genes involved in APL
..
15q22
.(15 ;17)(q22; q2 1)
gene
IIq23
,( II ;17)(q23;q21)
~t.~~~~~~9~E ~!~~it,i~1§%:~$.
ou:n:.-r."",
.... 1lT«
fOliDd.
Promyelo cyfic
zinc
leukemia
finger
(PLZF)Error! Reference source not found . Nucleophcsmin gene (NPM) t"" . .... _'" ~ ro,ud.~r",r · R~rne-~ 1oO"t-tf
loOffllUo1.
Nuclear
apparatus
wutn
5q35
~5 ;
17) (q 3S;q21)
gene
l lq 13
un ;17)(ql3;q2 I)
Sigmol transducer and activator of transcription Sb
17q21
derl7
mitotic
protein
(Nu..\f Af rrer' R"~rttlI< ... roell!.at fond.
gene (STAT
5b)l:rtW:Rtfl'nOU
MOfUJlDt fOlllld,.
ZI//balll, M.Biomed. r
Aio/eCN/ar Basi" 0 A CNte Prorm:
The rearrangement results in X-RARa. and RARa.-X fusion genes that encode for structurally
receptors, bound to RAREs more effici
different X-RARa and RARa-X proteins. The X-RAR causes an arrest of maturation at the promyelocytic stage of myeloid cell development and are oncogenic in vivo. The RAR-X are supposed to be not sufficient but do playa crucial role in leukemogenesis, by actin g both as tumor modifiers and tumor metamorphosers, and accelerate leukemia onset.
interact with a large ubiquitous nuclear c
RAR and Myeloid Differentiation RAR is a member of a class of nuclear recepto r proteins. Cells that overexpressed RAR displayed more prominently expressed myeloid differentiation markers and markedly decreased growth rate s. The secondary structure ofRAR is organized into modular functional units; an AlB domain with transcriptional activating functions, a DNA binding C domain containing 2 zinc fingers , a D hinge, and a complex El F dom ain that mediates ligand binding , dimerization, and interaction with co-repressor and co-activator tran scriptional proteins.
Recip rocal T mnslocahQTI
..
The PML gene and RAR gene is located on the long (q) arm of the chromosome 15 and 17 respectively (left). On the right, reciprocal translocation resulted in fusion gene (PML RAR gene and RAR-PML gene) . (a) PML in chromosome 15; (b) RAR in chromosome 17; (C) PML-RAR in chromosome 15; (d) RAR PML in chromosome 17. The RAR acts as ligand-inducible transcription fact or' and binds the retinoic acid response elements (RAREs)' in the DNA. A heterodime( of RAR with RXR, a member of a distinct famil y ofretinoic acid
RARJRAR or RXRlRXR homodimer. The
(NCoR) complex forming RAR-NCoR corn; the absence of RA, binding of RAR complex represses the transcription of ;: myeloid differentiation genes by recruiting deacetylases (HDACs) through NCoR 8 Phy siologi cal level s of RA (l0· M) are suffi : dissociate one corepressor complex from R:'\ recruits coactivators, and activate transcription. Moreover, other factors might play a ~ myeloid differentiation such as several cv: signa ling pathways, including Janus Ac: Kina s es/sign al tran sducer a n d acti va t transcription (JAKs/STAT ) and mitogen ac: protein serin e-threonine kinas es (MAPK). PML Gene and the Function oflts Protein Sequence anal ysis of the PML indicated the pre: of a cysteine -rich region that resembles a zinc- z., DNA binding domain and sugge sted the acti PML as a transcription factor. PML possesses gr suppressor and proapoptotic activity. Rearrangements Involving RAR and PML Gen Their Respective Fu sion Proteins Rearrangements can occur spontaneous : be induced by certain agents . Spontan rearrangement of the PML gene may occur ~ . bre akpoints of cluster region (bcr). Several s showed that breakpoints w ithin PM L intron 3 (b con sistently yielded a short fusion mRNA transc that j oins PMLexon 3 and RARa exon 3. Breakpoi within PML intron 6 (bcr 1) consistently produ . long transcript from the j oining of PML exon 6 RARa exon 3. Breakpoints within PML exon 6 (bcr ~ were associated with a variable length oftranscri . Agents that poi son s topoi somerase II could cause breakpoint within PML gene intron 6. The PML-RAR contains the N-terminal riz _ fing er and leucine zipper motifs of PML j oined to RAR B-F domains. Therefore, PML-RAR has ligand receptor domain for all tran s retinoic a _ (ATRA ). RAR-PML transcript is present in t _ majority, but not all, ofAPL cases.
hlolecular Basis of A cute PromyelocyticLeukemia
ZuJham. M.Biomed'
v than R also
Disruption of RAR and PML in the Pathogenesis of
)ressor
APLt(l5;17) The various X-RARa fusion proteins are
ex. In
always able to form heterodimeric complexes with the
NCoR rticular
respective X protein. As a consequence, these fusion proteins have the potential ability to interfere, at least
histone .mplex.
in theory, with both X and RARa pathways in a dominant negative manner, causing a decrease in
: ient to
transcription of differentiation factors. When the
uRAR,
partner gene involved PML, the RAR pathway was
. role in
heterodimerization with PML-RAR. Moreover,
-rosolic -tivated
PML-RAR disrupts the nonnallocation of the PML nucleanbody and interferes with the function ofPML:
of
The RAR and PML blockade is necessary, but not
crivated
sufficient, for leukemogenesis and the PML domain of
uor
he fusion protein provided unique functions that were required for leukemia initiation. As RAR, PML-RAR protein can interact resence
with NCoR complex to form PML-RAR-NCoR
-finger
complexes, The PML-RAR-NCoR complex was
tion of
shown to be more stable and resistant to physiological
5 growth
CONTROL ELEMENTS
uslyor
na ne ous
ur at 3
I studies .3 (ber 3) rranseript
-akpouns oduce -xon 6 te
6 (bcr J
anscripts.
ou gh two NCaR complexes from PML-RAR - modimers. Nuclear corepressor-bound histone : =acety lases were also tightly associated with PML <,-\R and PLZF-RAR fusion proteins. The histones of
zctively transcribed chromatin contain acetyl groups aat appear to loosens specific segments of DNA and
_..ow binding of specific transcription factors. - wever, histone deacetylases remove the acetyl _ 0UpS, tightens the specific segments of DNA, and :.asequently block transcription of gene that is cial for myeloid differentiation (Figure 2) .
caused
The distinct intracellular localization patterns
inal rin;
zpport the hypothesis that deregulation of these irtners may playa role in APL pathogenesis. The X
ed to th e
-_\R proteins localize to both the cytoplasm and
\. R has oic aci:
STRUCTURALGENE
Closed Chromatin
Fusion protein (i.e. PML-RAR protein) competes with the normal transcription factor and is bound to RAREs and NCoR that recruits HDACs. The protein eventually blocks the transcription of one of the primary target genes (blue), that are crucial for myeloid differentiation. H (HDAC), N (NcaR), P(PML), R(RAR).
,-\TRA than the RXRJRAR-NCoR complex. PML :l.<\R mediates stronger transcriptional repression
ie ne and ~
the nucleus but also to a lesser extent in the cytoplasm and displayed a microspeckled pattern. Figure 2. Schematic representation of transctiption blockade ofdifferentiation gene inAPL
damaged due to the sequestration of RXR by
I.
1
and STAT5b-RAR was mainly localized in
ac leu s . PML-RAR and PLZF -RAR shared ---:maryly diffuse nuclear pattern that excluded the
_cleolus. The NPM-RAR was also diffuse in, the _...Ieus but strongly associated with the nucleolus. : 'e NuMA-RAR was predominantly localized ..oughou t the cytoplasm in a microspeckled pattern,
Stat5b-RARaFusion Gene The generation ofStat5b-RARa is a rare event resulting from a small interstitial chromosome 17 deletion ranging from STAT5b intron n to RAR intron 2. STAT5b and RAR are very close to each other in 17q21.1-q21.2. Sequence analysis of STAT5b-RAR fusion gene showed a 3 bp insertion at the joining site; the 2.4 kb chimeric intron is mainly composed of STAT5b-derived intronic sequence. Stat5b-RARa fit the current paradigm that transcriptional repression is critical to the pathogenesis of certain types of human leukemia and offer further incentive for the development of rational drug therapy that can relieve this transcriptional repression by targeting HDACs or other members of the repressor complex.
APLMANAGEMENTSTRATEGY On the basis ofthe APL pathogenesis, current strategy of APL management are induction of APL cells differentiation," apoptotic induction of cells with incomplete cytodifferentiation,' and inhibition of HDACs acti vity ."
REFERENCES I. Pandolfi PP. Oncogenes and tumor suppressor in the molecular pathogenesis ofacute
Zillham,lvI.Biomed. '
promyelocytic leukemia. Human Molecular Genetics 2001;10(7):769-75. 2. Hummel JL, Zhang T, Wells RA, Kamel-Reid S. The retinoic acid receptor (RAR) chimeric proteins PML-, PLZF-, NPM-, and NuMA-RAR have distinct intracellular localization patterns. Cell Growth & Differentiation 2002; 13:173-83. 3. Soignet SL, Maslak P, Wang ZG, Janwar S, Calleja E, Dardashti LJ, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998;339(19): 1341-8. 4. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, Howe K, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Blood 2000;96(4): 1297-308. 5. Slack JL, Waxman S, Tricot G, Tallman MS, Bloomfield CD. Advances in the management of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide. Oncologist 2002;7: 1-13. 6. Pandolfi PP, Grignani F, Alcalay M, Mencarelli A, Biondi A, et al. Structure and origin of the acute promyelocytic leukemia myl/RAR cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 1991;6: 1285-92. 7. ChenZ, BrandNJ, ChenA, Chen S, TongJ, Wang Z, et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic receptor- locus due to a variant t(11;17) translocation associated with acute promyelocytic leukemia . EMBO J 1993;12:1161-7. 8. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5; 17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996;87(3):882-6. 9. Hummel JL, Wells RA, Dube ID, Licht JD, Kamel-Reid S. Deregulation ofNPM and PLZF in a variant t(5;17) case of acute promyelocytic leukemia. Oncogene 1999;18:633-41. 10. Wells RA, Kamel-Reid S. NuMA-RARA, a new gene fusion in acute promyelocytic leukemia. Blood 1996;88(suppl. 1):365a 11 . Arnould C, Philippe C, Bourdon V, Gregoire MJ, Berger R, Jonveaux P. The signal transducer and activator of transcription STAT 5b gene is a new in acute partner of retinoic acid receptor promyelocytic-like leukemia. Human Molecular Genetics 1999;8(9):1741-9.1. 1 2 Matsushita H, Scaglioni PP, Bhaumik M, Rego EM, Cai LF, Majid SM, et al. In vivo analysis of the role ofaberrant histone deacetylase
MolecularBasis of A cute Promye!oryticuukemia
recruitment and RAR a blockade in the pathogenesis of acute promye1ocytic leukemia. J Exp Med 2006;203(4):821-8 . 13. Redner RL, Chen JD, Rush EA, Li H, Pollock SL. The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties. Blood 2000;95(8):2683-90.
.-11
14. Leroy P,Nakshatri H, Chambon P.Mouse retinoic acid receptor 2 isofonn is transcribed from a promoter that contains a retinoic acid respons element. Proc. Natl. Acad. Sci. USA 1991;88: 10138-42. 15. Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, et al. PLZF-RAR fusion proteins generated from the variant t(11; 17)(q23;21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild type retinoic acid receptors. Proc. Natl. Acad. Sci. USA 1994;91: 1178-82.
-.=:
16. Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ. Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 2000;96(4): 1496-1503 .
- .;
17. Falini B, Flenghi L, Fagioli M, Coco FL, Cordone L, Diviero D. Immunocytochemicla diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibodyPG-M3 (Anti-PML). Blood 1997;90(10):4046-53. 18. Jurcic JG, Nimer SD, Scheinber DA, DeBlasio T, WaITeI Jr RP, Miller Jr WHo Prognostic significance ofminimal residual disease detection andPML/RAR-a isoform type: long-term follow up in acute promyelocytic leukemia. Blood 2001; 98(9):2651-6.
E
19. Mistry AR, Felix CA, Whitmarsh RJ, Mason Annabel, Reiter A, Cassinat B, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med 2005;352(15): 1529-38. 20. Yoshida H, Kitamura K, Tanaka K, et al. Accelerated degradation of PML-retinoic acid receptor (PML-RARA) oncoprotein by all-trans retinoic-acid in acute promyelocytic leukemia: possible role ofproteasome pathway. Cancer Res 1996;56:2945-8.
:
