Korean J Lab Med 2010;30: DOI /kjlm Original Article Diagnostic Hematology JAK2 V617F and Exon 12 Genetic Variations in Kor
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1 Korean J Lab Med 2010;30: DOI /kjlm Original Article Diagnostic Hematology JAK2 V617F and Exon 12 Genetic Variations in Korean atients with BCR/ABL1-negative Myeloproliferative Neoplasms Jeong Tae Kim, M.D. 1, Yong Gon Cho, M.D. 1, Sam Im Choi, M.D. 1, Young Jin Lee, M.D. 2, Hye Ran Kim, h.d. 3, Sook Jin Jang, M.D. 4,5, Dae Soo Moon, M.D. 4, Young Jin ark, M.D. 4, and Geon ark, M.D. 4,5 Department of Laboratory Medicine 1, Chonbuk National University Medical School, Jeonju; Department of Laboratory Medicine 2, Wonkwang University Medical School, Iksan; Brain Korea 21 roject 3, Center for Biomedical Human Resource at Chonnam National University, Gwangju; Department of Laboratory Medicine 4, Research Center for Resistant Cells 5, Chosun University Medical School, Gwangju, Korea Background : JAK2 genetic variations have been described in a high proportion of patients with BCR/ABL1-negative myeloproliferative neoplasms (MN). This study was designed to analyze the frequencies of JAK2 V617F and exon 12 variations, and their correlations with clinical characteristics of Korean patients with BCR/ABL1-negative MN. Methods : We examined a total of 154 patients with BCR/ABL1-negative MN that included 24, 26, 89, and 15 patients with polycythemia vera (V), primary myelofibrosis (MF), essential thrombocythemia (ET), and unclassified myeloproliferative neoplasms (MNU), respectively. We performed allele-specific CR to detect V617F in all BCR/ABL1-negative patients, and performed direct sequencing to detect exon 12 variations in 47 V617F-negative MN patients. JAK2 c _ 183del5 variation was detected by restriction fragment length polymorphism assay in 176 healthy subjects. Results : JAK2 V617F was detected in 91 patients (59.1%): V (91.6%), MF (46.2%), ET (52.8%), and MNU (66.7%). In V617F-negative MN patients, no mutations were found in exon 12. The c _183del5 was detected in 68.1% of V617F-negative MN patients and 45.4% of healthy subjects (=0.008). JAK2 V617F was closely correlated with age and leukocytosis in BCR/ABL1-negative MN patients (<0.05). However, c _183del5 was not related to age, sex, or complete blood cell count parameters in V617F-negative MN patients and healthy subjects. The c _183del5 was associated with an increased odds ratio for MN (odds ratio, 2.6; 95% confidences interval, ; =0.007). Conclusions : Frequencies of V617F are similar to reported results. JAK2 exon 12 mutations may be rare and c _183del5 may influence the occurrence of MN in Korean patients with V6 17F-negative MN. (Korean J Lab Med 2010;30:567-74) Key Words : Myeoloproliferative neoplasms, JAK2, V617F, Exon 12, rs Received : April 30, 2010 Manuscript No : KJLM Revision received : September 30, 2010 Accepted : October 14, 2010 Corresponding author : Geon ark, M.D. Department of Laboratory Medicine, Chosun University Medical School, 588 Seoseok-dong, Dong-gu, Gwangju , Korea Tel : , Fax : creatgeon@chosun.ac.kr *The present study was supported by grants from the Chosun University (2008). ISSN The Korean Society for Laboratory Medicine 서론골수증식종양 (myeloproliferative neoplasms, MN) 은골수에서한종류이상의골수세포 ( 과립구계, 적혈구계, 거대핵세포, 비만세포 ) 가증식하는조혈모세포의클론성질환이다 [1]. 만성골수성백혈병 (CML) 의경우 BCR/ABL1 융합유전자의발견으로진단과치료에큰발전을가져왔다 [2]. BCR/ABL1 음성 MN에서는질병특이적인표지자가발견되지않았으나최근 JAK2 유전자의엑손 14에위치하는 c.1849g>t 변이에의해 567
2 568 Korean J Lab Med 2010;30: 번아미노산이발린에서페닐알라닌으로치환되는점돌연변이 (V617F) 의발견으로 BCR/ABL1 음성 MN의진단과치료에있어서새로운길이열렸다 [3, 4]. 또한 539번째아미노산을중심으로 JAK2 엑손 12에위치하는다양한치환돌연변이가보고되고있다 [5]. BCR/ABL1 음성 MN에서 V617F 돌연변이에대한많은임상연구들이있다 [6-9]. 그러나, 한국인 BCR/ABL1 음성 MN 환자에서 JAK2 V617F에대한질환별연구는한차례있었으나검체수가적었고 [7], 한국인 MN 환자에서 JAK2 엑손 12 유전변이연구는보고된바가없었다. 또한엑손 12에인접한인트론 12에위치하는 c _183del5 (dbsn rs ) 유전변이와 BCR/ABL1 음성 MN 과의관련성이보고되었다 [10]. 이에저자들은한국인 BCR/ABL1 음성 MN 에서 V617F 유전자돌연변이빈도와돌연변이유무에따른임상적특성의차이를재확인하고 JAK2 엑손 12 및주변인트론부위 ( 특히, c _183del5) 의유전변이에대해정상인과비교하여살펴보고자한다. 대상및방법 1. 대상 1999년 7월부터 2007년 10 월까지호남지역에소재한세개의대학병원에서 MN으로새로진단받은환자 154명을대상으로하였으며진성적혈구증가증 (polycythemia vera, V) 24명 (15.6%), 일차골수섬유증 (primary myelofibrosis, MF) 26명 (16.9%), 진성혈소판증가증 (essential thrombocythemia, ET) 89명 (57.8%), 그리고미분류골수증식종양 (myeloproliferative neoplasm unclassified, MNU) 15 명 (9.7%) 이었다. 1999년부터 2001년사이진단된환자에대해서는 V와 ET 의경우 Thrombocythemia Vera Study Group의진단기준을따랐으며 [11], MF 의경우 Barosi 등 [12] 이제안한진단기준을따랐다. MNU의경우상기진단기준들을충족시키지못한경우분류하였다 년이후진단된환자에대해서는상기 4가지아형모두 WHO 진단기준 [13] 을따랐다. 그리고염색체검사에서필라델피아염색체음성인환자또는역전사중합효소연쇄반응법에의한 BCR/ ABL1 재배열음성인환자를대상으로하였으며각환자에대해병록지를조회하여성별, 연령, 일반혈액검사결과등을조사하였다. BCR/ABL1 음성 MN 환자군의성별구성은남성 84명 (54.5%), 여성 70명 (45.5%) 으로남성이많았으며평균연령과범위는 63세및 11-88세이었다 (Table 1). 건강검진을위해내원한수검자중에서정상판정을받은정상인중나이와성별을맞 Table 1. Clinical laboratory characteristics of the patients with BCR/ABL1-negative myeloproliferative disorders at the time of bone marrow examination and comparison of the clinical laboratory characteristics according to the mutational status of JAK2 V617F (N=10) (N=5) MNU (N=15) (N=47)) (N=42) ET (N=89) (N=12) (N=14) MF (N=26) (N=22) (N=2) V (N=24) (N=91) (N=63) Total Characteristics (N=154) Age (mean± 58.9± 52.6± 63.4± < ± 43.0± 61.0± ± 50± 72± ± 54.1± 64.0± ± 50± 53± SD, yr) Gender (M:F) 84:70 35:28 49: :12 2:0 10: :11 7:7 8: :40 23:19 26: :2 5: WBC ( 10 9 /L) 16.2± 12.3± 18.9± ± 4.9± 20.2± ± 11.5± 16.7± ± 14.7± 17.9± ± 10.1± 25.5± Hb (g/dl) 12.8± 12.1± 13.2± ± 18.1± 17.9± ± 9.3± 8.7± ± 11.1± 12.8± ± 8.1± 11.9± LT ( 10 9 /L) 807± 811± 804± ± 170± 548± ± 152± 295± ,109± 1,117± 1,101± ± 340± 579± Abbreviations: V, polycythemia vera; MF, primary myelofibrosis; ET, essential thrombocythemia; MNU, myeloproliferative neoplasms unclassified; WBC, white blood cell; LT, platelet.
3 Kim JT, et al., JAK2 V617F & Exon 12 Variations 569 춘 169명을대상으로 c _183del5 유전형을조사하였다. 정상인의성별구성은남성 88명 (50.0%) 및여성 88명 (50.0%) 이었으며평균연령과범위는 55.4세및 12-90세이었다. 본연구에대해윤리위원회의승인을받았다 (CBG- NIRB , 의임상제 호, IRB-10S-131). (Amresco, Solon, OH, USA) 600 ml를첨가하였다. 4 에서 14,000 rpm으로 15분간원심분리하고상층액을버린다음 70% 에탄올 600 ml로세척하였다. DNA 침전물 (pellet) 을실온에서건조시키고 DNA hydration solution (Gentra Systems) 20 ml으로녹여실험에이용하였다. 2. 골수도말슬라이드에서 DNA 추출 3. 대립유전자특이 CR 골수도말검체의 DNA는 uregene tissue core kit (Gentra Systems, Minneapolis, MN, USA) 를이용하여제조회사의지침과 Aplenc 등 [14] 의지침을참조하여추출하였다. 추출과정을간단히기술하면다음과같다. 실험에필요한 DNA를얻기위해염색된골수도말슬라이드 1-2장을이용하였다. 염색된골수도말슬라이드를자일렌에 3일동안담근후덮개유리슬라이드 (cover glass slide) 를제거하였다. 자일렌, 100% 및 70% 에탄올로순차적으로세척하였다. 인산완충식염수를슬라이드표면에적신후깨끗한유리슬라이드를이용하여긁어 1.5 ml 미세원침관에옮겨담았다. 이원침관에 cell lysis buffer (Gentra Systems) 600 ml와 20 mg/ml proteinase K (Gentra Systems) 3.0 ml를넣고 55 진탕항온수조에 12시간동안방치하였다. rotein precipitation buffer (Gentra Systems) 200 ml를넣은후 14,000 rpm으로 5분원심분리를시행하였다. 상층액을미세원침관으로옮겨담고 isopropanol SM DW JAK2 V617F 변이유무는대립유전자특이 CR (allele-specific CR) 을이용하여판정하였다 [8]. CR 반응물조제는 2 Anydirect Max Red premix (BioQuest, Seoul, Korea) 10 ml, 시발체혼합물 2 ml, 그리고 DNA 2 ml를사용하고최종반응량이 20 ml가되도록물을첨가하였다. Eppendorf Mastercycler (Eppendorf, Hamburg, Germany) 를이용하여증폭과정을수행하였으며 94 에서 5분반응시키고 94 에서 30초, 60 에서 30초, 72 에서 30초를 40회반복하고 72 에서 5 분간연장반응을시켰다. 양성및음성대조를위해 HEL (TIB-180; American Type Culture Collection, Manassas, VA, USA) 와염기서열분석으로확인한정상인 DNA를각각이용하였다 (Fig. 1). 4. JAK2 엑손 12와주변인트론에대한염기순서분석 V617F 음성 MN 환자에대해 JAK2 엑손 12와주변인트론에대한 CR-직접염기순서분석법을실시하였다. CR 증폭을 SM ,353 bp 872 bp 603 bp 310 bp 194 bp 364 bp 203 bp 1,353 bp 872 bp 603 bp 310 bp 194 bp 488 bp 327 bp 119 bp Fig. 1. The allele-specific CR assay for detecting JAK2 V617F mutation in patients with BCR/ABL1-negative myeloproliferative neoplasms. The 364 bp of CR product is an internal control and 203 bp is a mutant specific product. Lane SM, φx174/hindiii DNA size marker (TaKaRa, Siga, Japan); lane 1, JAK2 V617F mutation positive control; lane 2, JAK2 V617 wild negative control; lanes 3 and 6, positive results from clinical samples; lanes 4 and 5, negative results from clinical samples; lane D/W, deionized water. Fig. 2. The restriction fragment length polymorphism assay for detecting JAK2 c _183del5 genetic variation in normal subjects. Lane SM, φx174/hindiii DNA size marker (TaKaRa, Siga, Japan); lane 1, homozygotic wild control; lane 2, heterozygotic variant control; lane 3, homozygotic variant control; lane 4, homozygotic wild type; lane 5, heterozygotic variant type.
4 570 Korean J Lab Med 2010;30: 위해서 Je12F (5 -ctcctctttggagcaattca-3 ) 와 Je12R (5 -gggagttgcgatataggtctt-3 ) 를이용하였으며염기순서분석을위해 Je12sF (5 -ctttggagcaattcatacttt-3 ) 와 Je12sR (5 -agttgcgatataggtctttg-3 ) 를이용하였다. 본염기순서분석으로 c _183del5 이형접합 (heterozygote) 이아닌경우인트론 11에위치한 c 부터인트론 12에위치한 c 까지염기순서정보를얻을수있었다 (accession No. NM_ ). Eppendorf Mastercycler (Eppendorf) 와 AnyDirect Max Red premix (BioQuest) 를이용하여증폭과정을수행하였으며 94 에서 5분반응시키고 94 에서 30초, 50 에서 30초, 72 에서 30초를 35회반복하고 72 에서 5분간연장반응을시켰다. 정제된증폭산물을 BigDye Terminator v3.1 Cycle Sequencing kit (Applied Biosystems, Foster City, CA, USA) 와 ABI 3730XL Genetic Analyzer (Applied Biosystems) 을이용하여염기순서분석을시행하였다. 5. JAK2 c del5 유전자형분석정상인에서 JAK2 c _183del5 유전자형분석을위해제한효소절편길이다형성 (restriction fragment length polymorphism, RFL) 을실시하였다. JAK2 엑손 12 염기순서분석을위한증폭과정과동일하게증폭하였다. 정제된증폭산물을제한효소 aci (NEB, Japan, 10 U) 으로 37 에서 3시간처리하였다. 증폭산물을 aci 으로처리하면 JAK2 c.1641t 야생형인경우잘리지않고 (488 bp), c _183del5 대립유전자를가진변이형의경우 372 bp와 119 bp로잘리게된다 (Fig. 2). 6. 통계분석 JAK2 V617F 및 c _183del5 유전변이유무에따른연령및혈액학적지표와같은연속변수의차이를분석하기위해 Student s T 검정또는 Mann-Whitney U 검정을이용하였으며, 아형간연령의차이를분석하기위해 ANOVA 검정을이용하였다. 비연속변수간비교를위해 chi-square test 또는 Fisher s exact test을이용하였다. JAK2 c _183del5 유전변이의교차비 (odds ratio) 를분석하기위해단변량로지스틱회귀분석을실시하였다. 통계프로그램은 SSS version 17.0 (SSS Inc., Chicago, IL, USA) 를이용하였고 <0.05를통계적으로유의한것으로하였다. JAK2 V617F 음성환자군과대조군에서 c _183del5 유전자형의빈도가 Hardy-Weinberg 평형에따른분포를보이는지 Microsoft Office Excel 2010 (Microsoft Corp., Redmond, WA, USA) 을이용하여확인하였다. 결과 1. JAK2 V617F 변이빈도 JAK2 V617F 돌연변이빈도는 BCR/ABL1 음성 MN, V, MF, ET, 그리고 MNU 각각 91/154 (59.1%), 22/24 (91.6%), 12/26 (46.2%), 47/89 (52.8%), 그리고 10/15 (66.7%) 이었다. 2. JAK2 V617F 돌연변이유무에따른임상적특징비교 BCR/ABL1 음성 MN 환자의평균연령은 V617F 돌연변이양성군이 63.4세, 음성군이 52.6세로양성군에서통계적으로유의하게더높았다 (<0.001). 평균백혈구수는양성군 /L, 음성군 /L이었고(=0.003) 평균혈색소치는양성군 13.2 g/dl, 음성군 12.1 g/dl이었으며 (=0.418) 평균혈소판수는각각 /L, /L이었다(=0.935). 백혈구수는모든아형에서 V617F 양성군이더높았으며 V (=0.008) 와 MF (=0.004) 에서그차이가통계적으로유의하였다. 혈색소치는 ET의경우 V617F 양성군에서유의하게높았다 (=0.008) (Table 1). 3. JAK2 exon 12 및인접인트론유전변이 JAK2 V617F 돌연변이가검출되지않은 BCR/ABL1 음성 MN 56검체중직접염기분석이실시된 46검체에서 JAK2 exon 12 돌연변이는관찰되지않았다. V 환자 1명에서 JAK2 c.1557c>t 침묵유전변이가관찰되었다. V617F 음성 MN 환자에서 c _183del5 유전자형분포는 Hardy-Weinberg 평형을만족하지않았다 (χ 2 =4.82, =0.03). JAK2 c _183del5 유전변이가 63.0% (32/46) 에서관찰되었으며이형접합은 29명이었고동형접합 3명 (ET 2명, MNU 1명 ) 이었다. JAK2 c _183del5 유전변이의질환별빈도는 V 100% (1/1), MF 45.5% (5/11), ET 67.7% (23/32), 그리고 MNU 100% (3/3) 이었다. V617F 음성 MN 및 ET 환자에서 c _183del5 유전변이유무에따른연령, 성별, 혈색소, 백혈구수, 그리고혈소판수는통계적으로유의한차이가없었다 (Table 2).
5 Kim JT, et al., JAK2 V617F & Exon 12 Variations 571 Table 2. Clinical characteristics of patients with JAK2 V617F-negative myeloproliferative neoplasms and normal subjects according to the JAK2 c _183del5 (rs ) genetic variation MNU (N=3) Variant ET (N=32) Variant Variant MF (N=11) (N=6) V (N=1) Variant (N=1) Normal subject (N=176) Variant (N=0) (N=3) (N=5) (N=9) (N=23) (N=0) (N=96) (N=80) Total patients (N=47) Variant (N=32) Characteristic srs * (N=15) Age (mean±sd, yr) 56.2± ± ± ± ± ± ± ± ±1.7 Gender (M:F) 7:8 19: :49 41: :0 2:4 3:2 5:4 13: :1 WBC ( 10 9 /L) 16.2± ± ± ± ± ± ± ± ±4.9 Hb (g/dl) 16.2± ± ± ± ± ± ± ± ±3.3 LT ( 10 9 /L) 679± ± ± ± ± ± ,029±336 1,162± ±377 *JAK2 c.1641t wild type; JAK2 c _183del5 heterozygotic or homozygotic variant type. Abbreviation: V, polycythemia vera; MF, primary myelofibrosis; ET, essential thrombocythemia; MNU, myeloproliferative neoplasms unclassified; WBC, white blood cell; LT, platelet. 4. 정상인에서 c del5 유전변이분석정상인에서유전자형분포는 Hardy-Weinberg 평형을만족하였다 (c 2 =0.36, =0.55). 정상인 176명중 c _183del5 유전변이가 80명에서발견되었고 70명은이형접합이었으며 10 명은동형접합이었다. 정상인에서 c _183del5 유전변이유무에따른연령, 성별, 혈색소, 백혈구수, 그리고혈소판수는통계적으로유의한차이가없었으며 (Table 2) JAK2 c _183 이형접합군과동형접합군간의통계적유의한차이도관찰되지않았다 ( 분석결과제시하지않음 ). 5. c del5 교차비동형접합 c.1641t 야생형에대한이형접합및동형접합 c _183del5 변이형의교차비는 2.6 (95% 신뢰구간, ; =0.007) 으로 c _183del5 대립유전자를가지고있는경우골수증식종양의발생위험이야생형에비해통계적으로유의하게더높았다. 고찰 JAK2는 1,132개의아미노산으로구성된 131 KDa의 JAK 패밀리중하나이며 [15] 이단백질에대한유전정보는 9p24.1에존재한다 [16]. JAK2 유전자는 7개의도메인으로구성되어있으며 JAK homology 1 (JH1) 도메인은타이로신활성효소기능을소유하고있어서 JAK-STAT 신호전달에중심적인역할을하며 [17] 이와달리 JH2 도메인은가짜활성효소 (pseudokinase) 도메인으로서 JH1에의한신호전달의과항진 (overactivation) 을억제하는자가억제기능 (autoinhibitory function) 을가지고있다 [18]. JH2 도메인일부의유전정보를담고있는엑손 14에위치한 JAK2 V617F 돌연변이는신호전달의과항진을유발하여각수용체가표현되는세포의증식및분화를촉진한다 [19]. 본연구에서 BCR/ABL1 음성 MN의 JAK2 V617F 양성빈도는 59.1% 였다. JAK2 V617F 돌연변이빈도는성별에서는유의한차이를보이지않았다. 이는기존연구들과비슷한결과이다 [3, 8, 20, 21]. 그러나, JAK2 V617F 빈도는연령의증가와통계적으로유의하게관련이있었다. 이러한연령과의관련은기존연구에서도보고되고있는것이다 [3, 8, 20, 22]. 이는노화에따른수복유전자의변화로인한것으로생각해볼수있으나이에대한면밀한추가연구가필요할것으로사료된다.
6 572 Korean J Lab Med 2010;30: JAK2 V617F 양성 V에서백혈구수와혈소판수는통계적으로유의하게음성군보다더높았으나, 혈색소치의경우음성군이통계적유의성없이더높았다. V 에서 JAK2 V617F 돌연변이유무에따른혈색소치에대한다양한보고가있다 [23-25]. Barosi 등 [26] 은전섬유화단계 (prefibrotic stage) 를제외한 MF 환자 174명을대상으로수행한연구에서 JAK2 V617F 이형접합군은야생형군에비해혈색소치와혈소판수가통계적으로유의하게더높았으며 V617F 동형접합군과야생형군사이에는혈색소치와백혈구수가통계적으로유의한차이를보였다고하였다. 본연구에서는 JAK2 V617F의접합성에대해조사하지못했으나돌연변이양성군에서백혈구수 (=0.004) 와혈소판수 (=0.185) 가더높았다. 하지만혈색소치는오히려양성군에서더낮았는데이는본연구에서는전섬유화단계를포함하고있어서서로다른결과가보인것으로생각되었다. 본연구에서 ET는 52.8% 의 JAK2 V617F 양성률을보였다. 이는 23-74% 의양성률을보고한기존연구의평균값 (52.1%) 과비슷하였다. V617F 양성 ET 환자는음성환자에비해혈색소치가유의하게높았다 (=0.008). 150명을대상으로한연구에서 JAK2 V617F 양성군에서연령, 혈색소치, 백혈구수가통계적으로유의하게높았다고하였으며 [27] ET 환자를대상으로한또다른연구에서백혈구수와혈소판수가더높았으나통계적으로는유의하지않았다고하였다 [8]. JAK2 엑손 12는 JH2 도메인과 SH2 도메인의단백질합성을위한유전정보를가지고있다. 임상적으로엑손 12에위치한돌연변이는낮은혈장적혈구형성인자 (erythropoietin) 농도및 endogenous erythroid colony-forming cells의존재와관련있다고한다 [5]. BCR/ABL1 음성및 JAK2 V617F 음성 MN 환자를대상으로수행한기존연구에서엑손 12에위치한다양한돌연변이를보고하고있으나 [5, 19, 28-30] 본연구에서는엑손 12에돌연변이를발견할수없었다. 이는본연구대상에서 JAK2 V617F 음성 V 환자수가적어발견되지못하였을것으로생각된다. 더많은 V617F 음성 V 환자를대상으로추가연구가필요할것으로사료된다. 이와더불어, 인트론 12에위치한 c _183del5 유전변이가 JAK2 V617F 음성 MN 환자에서정상인보다유의하게더많이관찰되었다. 이유전변이는정상인에서도관찰되는유전변이로서 [31] 정상인및 MN 환자에서의빈도는알려져있지않다 [32]. 최근 JAK2 46/1 일배체형 (haplotype) 연구에서 c _183del5 유전변이가 46/1 일배체형과강하게연관되어있다고하였다 [10]. JAK2 46/1 일배체형은 c t >C (dbsn rs ; accession No. NM_ ) 단일 염기다형성을가진일배체로서 JAK2 V617F [33] 와 ML 유전자돌연변이 [10] 와연관되어있다는보고가있다. 본연구에서분석된교차비가 2.6이었으므로 MN의발생에 c _ 183del5가영향을끼칠것으로생각된다. 따라서, rs 과함께 rs 그리고 ML 돌연변이연구가추가로진행되어야할것으로사료된다. 한국인 BCR/ABL1 음성 MN에서기존연구와비슷한 V6 17F 돌연변이빈도와임상적특성이관찰되었다. 한국인 JAK2 V617F 음성 MN에서엑손 12 돌연변이는드물것으로생각되며 c _183del5 유전변이가 MN 발생과관련이있을것으로사료된다. 향후 JAK2 c _183del5에대한대규모의추가연구가필요할것으로사료된다. 요약배경 : JAK2 유전변이는 BCR/ABL1 음성골수증식종양환자에서높은빈도로발견된다. 본연구에서는 BCR/ABL1 음성골수증식종양환자의 JAK2 V617F와엑손 12 유전변이의빈도와임상적특성과의관련성을살펴보고자하였다. 방법 : BCR/ABL1 음성골수증식종양환자 154명 ( 진성적혈구증가증 (polycythemia vera, V) 24명, 일차골수섬유증 (primary myelofibrosis, MF) 26명, 진성혈소판증가증 (essential thrombocythemia, ET) 89명, 그리고미분류골수증식종양 (myeloproliferative neoplasms unclassified, MNU) 15 명 ) 을대상으로하였다. BCR/ABL1 음성골수증식종양환자에서 JAK2 V617F 돌연변이를검출하기위해대립유전자특이중합효소연쇄반응법을실시하였으며 47명의 V617F 음성골수증식종양환자에서엑손 12 유전변이를검출하기위해직접염기순서분석을실시하였다. 176명의정상인을대상으로 JAK2 c _183del5 유전형을결정하기위해제한효소절편길이다형성을실시하였다. 결과 : JAK2 V617F는 91명 (59.1%) 에서관찰되었다. V (91.6%), MF (46.2%), ET (52.8%), 그리고 MNU (66.7%). JAK2 V617F 음성골수증식종양환자에서 JAK2 엑손 12 돌연변이는관찰되지않았다. V617F 음성골수증식종양환자에서 JAK2 c _183del5 유전변이는 68.1% 에서발견되었으며정상인에서는 45.4% 에서발견되었다 (=0.008). BCR/ABL1 음성골수증식종양환자에서 JAK2 V617F는나이와백혈구증가증과관련이있었다 (<0.05). 그러나 V617F 음성골수증식종양환자와정상인에서 c _183del5 유전변이는나이, 성별, 그리고총혈구계산지수와상관이없었다. JAK2 c.1641+
7 Kim JT, et al., JAK2 V617F & Exon 12 Variations _183del5은 MN에서증가된교차비 ( 교차비, 2.6;95% 신뢰구간, ; =0.007) 를보였다. 결론 : JAK2 V617F 돌연변이빈도는기존보고와유사하였다. 한국인 V617F 음성골수증식종양에서엑손 12 돌연변이는드물것으로생각되며 c _183del5는골수증식종양의발생에영향을끼치는것으로사료된다. 참고문헌 1. Tefferi A and Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22: Kurzrock R, Kantarjian HM, Druker BJ, Talpaz M. hiladelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann Intern Med 2003;138: Kralovics R, assamonti F, Buser AS, Teo SS, Tiedt R, assweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352: Tefferi A and Gilliland DG. Oncogenes in myeloproliferative disorders. Cell Cycle 2007;6: Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. Int J Hematol 2010;91: Ahn JY, Yoo SJ, Bang SM, ark W, Seo YH, Shin DB, et al. JAK2 V617F mutation in Korean patients with essential thrombocythemia. Korean J Lab Med 2007;27: ( 안정열, 유수진, 방수미, 박필환, 서일혜, 신동복등. 한국인본태성혈소판혈증환자에서 JAK2 V617F 유전자변이. Korean J Lab Med 2007;27:77-82.) 7. Bang SM, Ahn JY, ark J, Yoo SJ, ark SH, Nam EM, et al. Diagnostic usefulness of the Janus kinase 2 mutation in non BCR/ABL myeloproliferative disorders. Korean J Intern Med 2006;21: Baxter EJ, Scott LM, Campbell J, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365: Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106: Jones AV, Campbell J, Beer A, Schnittger S, Vannucchi AM, Zoi K, et al. The JAK2 46/1 haplotype predisposes to ML-mutated myeloproliferative neoplasms. Blood 2010;115: Michiels JJ and Juvonen E. roposal for revised diagnostic criteria of essential thrombocythemia and polycythemia vera by the Thrombocythemia Vera Study Group. Semin Thromb Hemost 1997;23: Barosi G, Ambrosetti A, Finelli C, Grossi A, Leoni, Liberato NL, et al. The Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia. Br J Haematol 1999;104: Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002; 100: Aplenc R, Orudjev E, Swoyer J, Manke B, Rebbeck T. Differential bone marrow aspirate DNA yields from commercial extraction kits. Leukemia 2002;16: Saltzman A, Stone M, Franks C, Searfoss G, Munro R, Jaye M, et al. Cloning and characterization of human Jak-2 kinase: high mrna expression in immune cells and muscle tissue. Biochem Biophys Res Commun 1998;246: Quentmeier H, MacLeod RA, Zaborski M, Drexler HG. JAK2 V617F tyrosine kinase mutation in cell lines derived from myeloproliferative disorders. Leukemia 2006;20: Watanabe S and Arai K. Roles of the JAK-STAT system in signal transduction via cytokine receptors. Curr Opin Genet Dev 1996;6: Saharinen, Takaluoma K, Silvennoinen O. Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Mol Cell Biol 2000;20: ercy MJ, Scott LM, Erber WN, Harrison CN, Reilly JT, Jones FG, et al. The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica 2007;92: Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7: Speletas M, Katodritou E, Daiou C, Mandala E, apadakis E, Kioumi A, et al. Correlations of JAK2-V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders. Leuk Res 2007;31: Levine RL, ardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007;7: Bousquet M, Le Guellec S, Quelen C, Rigal-Huguet F, Delsol G, Brousset. Frequent detection of the JAK2 V617F mutation in bone ma-
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