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1 대한내과학회지 : 제 75 권제 4 호 2008 급성전골수구성백혈병에서 PML/RARα 유전자이형의임상적의의 인제대학교의과대학내과학교실부산백병원 1, 울산대학교의과대학내과학교실서울아산병원 2, 울산대학교병원내과학교실 3, 대구가톨릭대학교의과대학내과학교실 4, 영남대학교의과대학내과학교실 5, 한림대학교의과대학내과학교실 6, 성균관대학교의과대학내과학교실삼성서울병원 7, 경상대학교의과대학내과학교실 8, 대구파티마병원 9 이원식 1 이상민 1 이규형 2 이제환 2 최성준 2 이정희 2 김대영 2 임성남 2 박재후 3 민영주 3 김혁 3 배성화 4 류헌모 4 현명수 5 김민경 5 장대영 6 김효정 6 정철원 7 안진석 7 이경원 8 이정림 9 주영돈 1 Clinical significance of PML/RARα isoforms in acute promyelocytic leukemia Won Sik Lee, M.D. 1, Sang Min Lee, M.D. 1, Kyoo-Hyung Lee, M.D. 2, Je-Hwan Lee, M.D. 2, Seong-Joon Choi, M.D. 2, Jung-Hee Lee, M.D. 2, Dae-Young Kim, M.D. 2, Sung-Nam Lim, M.D. 2, Jae Hoo Park, M.D. 3, Young Joo Min, M.D. 3, Hawk Kim, M.D. 3, Sung Hwa Bae, M.D. 4, Hun Mo Ryoo, M.D. 4, Myung Soo Hyun, M.D. 5, Min Kyung Kim, M.D. 5, Dae Young Zang, M.D. 6, Hyo Jung Kim, M.D. 6, Chul Won Jung, M.D. 7, Jin Seok Ahn, M.D. 7, Kyeong Won Lee, M.D. 8, Jung Lim Lee, M.D. 9 and Young-Don Joo, M.D. 1 Department of Internal Medicine, Inje University College of Medicine 1, Busan Paik Hospital, Pusan, Korea; Department of Internal Medicine, University of Ulsan College of Medicine 2, Asan Medical Center, Seoul, Korea; Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine 3, Ulsan, Korea; Department of Internal Medicine, Daegu Catholic University College of Medicine 4, Daegu, Korea; Department of Internal Medicine, Yeungnam University College of Medicine 5, Yeungnam, Korea; Department of Internal Medicine, Hallym University College of Medicine6, Seoul, Korea; Department of Internal Medicine, Samsung Medical Center 7, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Internal Medicine, College of Medicine, Gyeong-Sang National University 8, Gyeongsang, Korea; Department of Internal Medicine, Daegu Patima Hospital 9, Daegu, Korea Background/Aims: There are three types of PML-RARα mrna fusion transcripts associated with acute promyelocytic leukemia (APL): the short (S)-form, the long (L)-form and the variable (V)-form. No study on the Korean population has addressed the clinical significance of the specific types of PML-RARα mrna fusion transcripts for APL patients who receive the combination therapy of all-trans-retinoic-acid and idarubicin (AIDA regimen). Methods: We performed a retrospective analysis on 94 patients with APL to evaluate differences in the therapeutic outcomes, such as the response rate, an event-free survival (EFS), and overall survival (OS), after remission following the induction of chemotherapy. We also analyzed whether differences in the pretreatment clinical characteristics depend on the PML-RARα isoform. Results: The median age of the patients was 41 years (range 15-85). Among the 94 patients, there were 58 L-form cases (62.1%), 32 S-form cases (34.0%), and 4 V-form cases (4.3%). The CR rate following remission induction treatment was 84.9%. The CR rate was higher in patients with an initial WBC < /L, as compared to patients with an initial WBC higher than /L (93.5% vs. 65.4%, p=0.001). The AIDA induction regimen was associated with a better EFS than non-aida induction regimens (81.9% vs. 49.6%, p=0.006). The induction group was also a significant prognostic factor for EFS in the multivariate analysis (p=0.020). There were no differences in OS and EFS in patients with either isoform L or isoform S in the AIDA induction group. Conclusions: This retrospective study demonstrated that pretreatment clinical characteristics and treatment outcomes were not significantly different among patients with varying PML-RARα isoform types in the AIDA induction group. (Korean J Med 75: , 2008) Key Words: Acute promyelocytic leukemia; PML-RARα; Isoform Received: Accepted: Correspondence to: Young-Don Joo, M.D., Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Gaegeum2-dong, Busanjin-gu, Busan , Korea yjoo@inje.ac.kr *This work was supported by grant from Inje University,

2 - Won Sik Lee, et al: PML/RARα isoforms in APL - 서 론 등을후향적으로분석하였다 17). 15번, 17번염색체의전좌를통한 PML (15q22) 과 RARα (17q21) 유전자의융합은급성전골수구성백혈병의발병과밀접한연관성을가진다 1). PML/RARα 유전자에대한역전사중합효소연쇄반응 (Reverse transcriptase-polymerase chain reaction: RT-PCR) 은 PML/RARα 유전자이형에대한정보제공과미세잔류백혈병세포의발견등급성전골수구성백혈병의유전적진단에널리이용되고있다 1). 그외동등한특이성을가지는검사기법으로형광제자리부합화분석 (fluorescence in situ hybridization analysis: FISH) 과특이항체를이용한급성전골수성백혈병면역염색법등이있다 2, 3). PML- RARα mrna 융합전사물은세가지형태로만들어질수있는데, 그이유는 PML 유전자의절단점이 intron 3, intron 6, 또는 exon 6로각각다르기때문이다. RARα 유전자의절단점인 intron 2와 PML유전자의 intron 3 절단점이융합하면길이가짧은 (short type, S형 ) 전사물이생성되고, PML 유전자의 intron 6에절단점이위치하면길이가긴 (long type, L 형 ) 융합전사물이생겨난다. 드물게절단점이 PML exon 6에위치할경우 L형보다는길이가약간짧은변형 (variant type, V형 ) 의융합전사물이생성된다 4, 5). 급성전골수구성백혈병은세포분화를유도하는 all-transretinoic-acid (ATRA) 에반응을보이기때문에대상환자의 PML-RARαmRNA 유형에따른임상소견및치료반응의차이등은매우중요한연구대상이될수있다 6, 7). PML- RARα 유전자이형의다양성은 ATRA 매개신호전달에참여하는다른거대분자와의상호작용에도영향을미치고, 치료반응의차이도유발할수있다 4, 8). PML-RARα 유전자이형에따라서임상소견의차이가있다는보고와임상소견또는치료반응과는관련이없다는보고가있었으나, 이들은대부분관해유도요법으로 ATRA단독요법또는전통적인항암화학요법을사용했던경우였다 9-12). Stock 등 13) 은 L형 PML- RARα융합유전자이형을가진환자군에서무사건생존율이높다고보고를하여서이에대한재평가가필요한실정이다. 이에저자는급성전골수구성백혈병의표준관해유도요법으로인정되는 AIDA요법 (ATRA 45 mg/m 2 을하루 2회씩분복하여완전관해유도시점또는최대 90일까지경구투여하고 idarubicin 12 mg/m 2 을제 2, 4, 6, 8일째정주하는병합요법 ) 을받은환자들을주요대상으로하여 PML-RARα 융합유전자이형에따른임상소견과치료에대한반응의차이 대상및방법 1. 대상환자의선정 1998년부터 2006년까지인제대학교부산백병원과울산대학교서울아산병원을포함하여총 9개병원에내원하여급성전골수구성백혈병으로진단받은환자들을연구대상으로선정조건은다음과같다. 연령이 15세이상으로이전에급성전골수구성백혈병으로치료받은적이없는환자로 PML/ RARα 유전자에대한 RT-PCR이양성이고, PML-RARα mrna 분석결과이용및추적관찰이가능했던경우를대상으로하였다. 2. 분석방법급성전골수구성백혈병의진단시연령, 성별, 임상증상, 말초혈액에서의세포감별계산, 골수검사소견등과같은혈액학적자료, 세포유전학적검사및면역표현형, RT-PCR 분석및 PML-RARα 융합유전자이형의종류, 관해유도치료방법과반응, 재발여부등을후향적으로환자의병록지및검사소견을검토하여확인하고생존여부는마지막방문이나전화로확인하여기록하였다. 이를바탕으로 PML-RAR α융합유전자이형의유형별로임상소견의차이를분석하였다. 그리고관해유도치료방법으로 AIDA요법을사용한환자군에서 PML-RARα 융합유전자이형의유형에따른차이, 완전반응률, 전체생존율과무사건생존율등을조사하였다. 완전반응은혈액학적완전반응으로미국국립암연구소의기준을따라정의하였다 14). 전체생존기간은치료를시작한날로부터사망하거나혹은최종적으로외래통원치료를받은날까지의기간으로하였고, 무사건생존기간은치료를시작한날로부터재발또는진행이최초로확인된날혹은사망이확인된시점으로하였다. 통계분석을위하여 SPSS version 11.0을사용하였다. PML- RARα 융합유전자이형에따른임상적소견및완전반응률의차이는 chi-square 검사를하였고, 전체생존률과무사건생존률은 Kaplan-Meier 방법으로계산하였으며, 생존기간의비교는단변량분석에는 log-rank test, 다변량분석에는 cox proportional hazard model을이용하여비교하여 p<0.05일때를유의하다고판정하였다

3 - 대한내과학회지 : 제 75 권제 4 호통권제 578 호 Table 1. Clinical characteristics of all the patients (n=94) Age, (median range) 41 (15-85) Gender Ratio (M/F) 1 : 1.41 (39/55) % presenting with WBC > /L 29 median range 0.19,161.4 % of patients presenting with platelet 54.3 < /L median range FAB classification N (% of patients) M3 87 (92.6) M3v 4 (4.3) PML-RARα isoform type N (% of patients) L-form 58 (61.7) S-form 32 (34) V-form 4 (4.3) 결과 1. 임상소견전체 94명환자의중앙연령은 41세 ( 범위, 15~85세 ) 이고, 남녀비는 1:1.41(39:55) 이었다 ( 표 1). 진단시출혈이 19명 (20.4%), 빈혈이 10명 (10.8%), 발열이 25명 (27.2%) 에서보였고, 체중감소가 10명 (10.8%) 에서보였다. 진단당시평균백혈구수치는 15.32± /L, 평균혈색소는 8.04±0.4 mg/dl, 평균혈소판수치는 40.96± /L이었다( 표 1). 진단시말초혈액에서전골수구와골수모세포비율을합산한평균은 37.3% (0~97%) 이었다. 진단은 FAB분류법으로 M3가 87명 (92.6%), M3v가 4명 (4.3%) 였고, 3명은불분명하였다. PML-RARα 융합유전자이형은 L형이 58예 (61.7%), S형이 32예 (34%), V형이 4예 (4.3%) 이었다 ( 표 1). V형은숫자가너무작아임상적특징및치료결과에대한비교분석에서는제외하였다. PML-RAR α융합유전자이형별로임상적특징을비교분석한결과통계적으로유의한차이를보이는인자는없었다 ( 표 2). 2. 관해유도요법관해유도요법은 AIDA요법 71명 (75.5%), 비AIDA요법 22 명 (23.4%) 이었고, 1명은뇌출혈로인한조기사망으로관해유도를시행하지못하였다. 관해유도횟수는 1회가 91명 (96.8%), 2회가 2명 (2.2%) 이었다. 관해유도에대한반응은완전반응이 79명 (84.9%), 불응성이 14명 (15.1%) 이었다. 완전반응에도달하는데걸린시간은 36.7±2.37일이었다. 관해유도후중성구가 /L이상도달하는데걸린시간은 26.9± 2.0일이었고, 혈소판이 /L이상도달하는데걸린시간은 26.2±2.2일이었다. 불응성인경우는골수독성으로인한합병증으로 13명이사망하였으며, 관해유도치료에반응하지않았던경우가 1명이었다. 완전반응과임상소견과의연관관계를분석한결과진단당시백혈구수가 /L 이하인경우 (p=0.001) 가완전반응률이유의하게높았지만, PML- RARα융합유전자이형에따른완전반응률은 L형이 84.2%, S형이 87.2% 로통계적으로유의한차이는관찰되지않았다. AIDA요법으로관해유도를받은 71명의중앙연령은 41세 ( 범위, 15~85세 ) 이고, 남녀비는 1:1.54 (28:43) 였다. AIDA요법을시행받은군에서의 PML-RARα 융합유전자이형의분포는 L형이 42예 (59.2%), S형이 27예 (38.0%), V형이 2예 (2.8%) Table. 2 Clinical characteristics according to PML-RARα isoform type Sex (male) (%) Age (median, year) M3v (%) Presenting bleeding symptom (%) Weight loss (%) Fever (%) PB * WBC count at diagnosis > /L (%) PB * platelet count at diagnosis < /L (%) PB * promyelocyte plus myeloblast count at diagnosis > 20% (%) * peripheral blood L-type S-type p value

4 - 이원식외 21 인 : 국문제목급성전골수구성백혈병에서 PML/RARα 유전자이형 - Table 3. Analysis of response to induction chemotherapy according to pretreatment prognostic factor Factors Patients CR * Rate (%) p-value Age (yrs) > Gender Male Female FAB classification M M3v Presenting bleeding symptom Yes No Weight loss Yes No Fever Yes No PB WBC count at diagnosis ( 10 9 /L) > PB platelet count at diagnosis ( 10 9 /L) > AIDA induction therapy Yes No PML-RARα isoform L-type S-type * complete response, peripheral blood. 였다. AIDA요법을시행받은군에서도 PML- RARα 융합유전자이형에따른치료전임상소견의차이는없었다 ( 표 4). AIDA요법시행후완전관해율은 L형이 83.7%, S형이 92.3% 였으나, 통계적으로유의한차이는없었다 (p=0.501). 전체적으로완전관해에도달한 79명중공고요법을시행한경우는 76명 (96.2%) 였다. 그중 29명이 3차례, 46명이 2차례, 1명이 1차례의공고요법을시행받았다. 또한공고요법시 ATRA를투여받은경우는 57명 (75.0%) 이었다. 공고요법을시행한 76 명중에서유지요법이시행된경우는 63명 (82.9%) 이었고, 평균기간은 17.5개월 (1~36개월) 이었다. 3. 생존기간추적관찰기간의중앙치는 27개월이었으며생존기간은 0~90개월이었다. 5년전체생존률은 77.7% 였고, 전체생존기간의중앙치에는도달하지않았다. 전체적으로 21명이사망하였는데, 사망원인은뇌출혈로인한조기사망 1명, 관해유도중골수기능부전으로인한합병증 13명, 병의진행 5명, 기타 2명이었다. PML-RARα 융합유전자이형에따른 5년전체생존율은 L형이 74.3%, S형이 83.1% 로통계적으로유의한차이는관찰되지않았다 (p=0.165) ( 그림 1A). 관해유도요법에따른 5년전체생존율은 AIDA군이 84.4%, 비AIDA군이 58.4% 였으나, 통계적으로유의하지는않았다 (p=0.056). 그외임상적특징도유의한차이를보이는경우는없었다. 완전관해에도달한 79명중재발여부를확인할수있었던경우는 75명으로이중 6명 (8.0%) 에서재발하였다. PML-RARα 융합유전자이형에따른재발은 L형 3예 (6.5%), S형 3예 (10.3%) 였으나, 통계적으로유의하지는않았다 (p=0.875). 관해유도요법에따른재발은 AIDA군이 2명 (3.3%), 비AIDA군이 4명 (26.7%) 으로통계적인유의한차이가있었다 (p=0.014). 전체 Table 4. Clinical characteristics according to PML-RARα isoform type in AIDA group Sex (male) (%) Age (median) M3v (%) Presenting bleeding symptom (%) Weight loss (%) Fever (%) PB* WBC count at diagnosis > /L (%) PB* platelet count at diagnosis < /L (%) PB* promyelocyte plus myeloblast count at diagnosis > 20% (%) * peripheral blood L-type S-type p-value

5 - The Korean Journal of Medicine: Vol. 75, No. 4, p=0.165 p=0.198 A B Figure 1. Survival curves for the acute promyelocytic leukemia patients according to PML-RARα isoform type. (A) overall survival, (B) event-free survival. p=0.210 p=0.177 A B Figure 2. Survival curves for AIDA induction therapy group according to PML-RARα isoform type. (A) overall survival, (B) event-free survival. 환자의 5년무사건생존률은 72.8% 였고, 무사건생존기간의중앙치에는도달하지않았다. PML-RARα 융합유전자이형에따른 5년무사건생존율은 L형이 68.5%, S형이 78.9% 로통계적으로유의한차이는관찰되지않았다 (p=0.198) ( 그림 1B). 관해유도요법에따른 5년무사건생존율은 AIDA군이 81.9%, 비AIDA군이 49.6% 이었다 (p=0.006). 다변량분석에서관해유도요법 (p=0.020) 만이통계학적으로의미있는예후인자였다. AIDA군에서 5년전체생존율은 L형이 81.8%, S형이 92.3% 이고 (p=0.210) ( 그림 2A), 5년무사건생존율은 L형이 74.0%, S형이 92.3% 로 (p=0.177) ( 그림 2B) 각각통계적으로유의한차이가없었다. 고찰급성전골수구성백혈병은 t(15;17)(q22;q21) 염색체전좌에의한 PML-RARα 융합유전자생성이주요병인이다. 치료에 ATRA를이용하는분화요법이도입되면서완전관해율이높아졌을뿐아니라응고장애및치명적출혈등의합병증으로인한사망을획기적으로줄일수있었다 15). 하지만관해유도요법으로 ATRA 단독투여시레틴산증후군등의합병증과저항성으로인한재발율이 20~30% 정도로높아서세포독성항암제와 ATRA를동시에투여하는방법이표준요법으로되었다 16). GIMEMA연구에서관해유도시 idarubicin을 ATRA와병합하고공고요법시에세가지의 anthra

6 - Won Sik Lee, et al: PML/RARα isoforms in APL - cycline계열의항암제를투여하는 AIDA요법으로이전요법에비해연장된무사건생존기간을보고하여현재까지표준요법으로자리잡고있다 17, 18). 본연구에서도 AIDA요법군이비AIDA요법군에비하여완전관해율은차이가없었으나 (p=0.438), 무사건생존율은의미있게높았다 (p=0.006). 다뱐량분석에서도 AIDA요법군이무사건생존율의유일한중요예후인자였다 (p=0.020). 하지만두군간의임상적특징이차이가있고, 비AIDA요법군의일부는신체활동도가좋지못하여 ATRA만투여했던경우도존재하여객관적비교는힘들었다. 급성전골수구성백혈병에서 RT-PCR로검출되는 L형, S형, V형의 PML-RARα 융합유전자유형들의빈도는 L형이 S 형보다는빈도가많고, L형대 S형의비율이 1.7~5.5 정도로다양하게보고되고있다 9, 11, 19). 본연구에서 L형은 62.1% 였고, 이등 20) 이보고한 62.6%, Gallagher 등 12) 이보고한 55% 와비슷하였다. V형은비교적드물지만 3~20% 로다양하게보고되는데염기서열을확인하지않으면 L형에포함될수있다 21, 22). Gallagher 등 12) 은 V형의빈도가 8% 라고보고하였다. 본연구에서도 V형의빈도는 4.3% 로유사하였다. V형은치료전백혈구수가높은경향을보이고, 비전형적인면역표현형을나타내기도한다 21). PML-RARα 융합유전자이형과임상소견의관련성을분석한결과의미있게차이를보이는치료전임상소견은없었다. Gallagher 등 12) 은 S형이 L형에비하여치료전백혈구수치가높은경우가많았다고보고하였고, AIDA 관해유도요법을사용한환자를대상으로한 PETHEMA 연구 23) 에서도 S형에서치료전백혈구수치가높다고보고하였다. 하지만치료전높은백혈구수치와 PML- RARα 융합유전자이형사이에는연관성이없다는보고도있었다 24). 본연구에서는통계적으로유의하지는않았지만전체대상환자에서 S형이치료전백혈구수 /L 이상인경우가많은경향을보였다 (40.6% vs 22.8%, p=0.076). 그리고 S형에서말초혈액의미성숙백혈구 ( 모세포와전골수구의합 ) 가높고, M3v 가더많다는보고가있었다 12, 25). 본연구에서는 S형에서말초혈액의미성숙백혈구수, M3v 빈도등에있어차이점이나타나지않았다. 급성전골수구성백혈병에서는치료전백혈구수치가높으면관해유도요법에대한완전관해율이낮은것으로알려져있다 26, 27). 본연구에서도치료전백혈구수치가 /L 이상인경우완전관해율이현저히낮았지만 (93.5% vs. 65.4%, p=0.001), PML-RARα 융합유전자이형에따른완전관해율의차이는발견되지않았다. 이는이전연구들에서의결과와유사하였다 12, 13, 19, 23). S형 에서치료전백혈구수치가높은경향을보였지만, 완전관해율에큰차이가없었던점은 S형에서완전관해율이높은 AIDA관해유도요법의빈도가높았던점이일부기인하였을것으로생각된다. Stock 등 13) 이관해유도요법으로 ATRA와 cytarabine, daunorubicin을병합하고, 필요하면 arsenic trioxide 를투여하는연구에서 L형이 S형에비해무사건생존율이통계적으로유의하게높다고보고를하였다. Gallagher 등 12) 도 L형에서치료중조기사망이나재발율이낮아서, 무사건생존율이높은경향을보인다고보고한바있다. AIDA요법을시행한환자를대상으로한 PEPHEMA연구 24) 에서는비록통계적유의성은없지만, V형에서무사건생존율이낮은경향을보인다고하였다. 그러나 Fukutani 등 29) 은관해율, 생존률, 관해기간및생존기간에있어서 S형과 L형간에유의한차이가없으므로급성전골수구성백혈병에서 ATRA 치료후의반응은 PML-RARα 융합유전자이형과관련이없다고하였다. 본연구에서는 V형은빈도가낮아비교하기어려웠고, L형과 S형에서는 PML-RARα 융합유전자이형에따른무사건생존율의차이는나타나지않고 S형에서무사건생존율이약간높은경향을보였지만 ( 그림 1B, p=0.198, 그림 2B, p=0.177), PML-RARα 융합유전자이형과생존율은관련성이없다고판단되었다. 결론적으로급성전골수구성백혈병환자에서 PML-RARα 융합유전자이형의임상적중요성은 AIDA요법을관해유도로사용한군을포함해서전체환자군에서발견할수가없었다. PML-RARα 융합유전자이형의임상적중요성을더정확하게검증하기위해서는보다잘계획된전향적연구가필요하리라생각된다. 요약목적 : 급성전골수구성백혈병은 L형, S형, V형의세가지형태 PML-RARαmRNA 융합전사물이만들어질수있다. PML-RARαmRNA 융합전사물이형에따른임상적소견과치료결과의연관성에관한여러연구에서상반된결과들이보고되었고, 관해유도요법으로 AIDA 요법을시행받았던환자들을대상으로한연구는국내에서보고된적이없었다. 방법 : 급성전골수구성백혈병으로진단받고 PML-RARα 유전자이형이확인된 94명의환자를대상으로후향적분석을시행하여, PML-RARα 유전자이형에따른치료전임상소견과관해유도요법에따른치료결과의차이를반응률과무사건생존율, 전체생존율에대해비교분석하였다. 결과 : 전체환자의중앙연령은 41 (15~85) 세였다. 총

7 - 대한내과학회지 : 제 75 권제 4 호통권제 578 호 명의환자중 L형은 58예 (62.1%), S형은 32예 (34.0%), V형은 4예 (4.3%) 였다. PML-RARα 유전자이형에따라유의한차이를보이는치료전임상소견은없었다. 완전관해율은초기백혈구수치가 /L 이하인경우에서유의하게높았다 (93.5% vs. 65.4%, p=0.001). AIDA 군은비AIDA군에비하여 5년무사건생존율이더높았고 (81.9% vs 49.6%, p=0.006), 다변량분석에서도관해유도요법의유형은무사건생존율의중요한예후인자였다 (p=0.020). AIDA 군내에서 PML-RARα 유전자이형에따른 5년전체생존율과무사건생존율의차이는없었다. 결론 : 본연구에서는 PML-RARα 유전자이형에따른치료전임상적소견과치료결과는 AIDA군에서차이를보이지않았고, 정확한검증을위해서는잘계획된전향적연구가필요하리라생각된다. 중심단어 : 급성전골수구성백혈병 ; PML-RARα, 이형 REFERENCES 1) Diverio D, Riccioni R, Mandelli F, Lo Coco F. The PML/RAR alpha fusion gene in the diagnosis and monitoring of acute promyelocytic leukemia. Haematologica 80: , ) Grimwade D, Howe K, Langabeer S, Davies L, Oliver F, Walker H, Swirsky D, Wheatley K, Goldstone A, Burnett A, Solomon E. Establishing the presence of the t(15;17) in suspected acute promyelocytic leukaemia: cytogenetic, molecular and PML immunofluorescence assessment of patients entered into the M.R.C. ATRA trial. M.R.C. Adult Leukaemia Working Party. Br J Haematol 94: , ) Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, Pasqualucci L, Biondi A, Riganelli D, Orleth A, Liso A, Martelli MF, Pelicci PG, Pileri S. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-pml). Blood 90: , ) Pandolfi PP, Alcalay M, Fagioli M, Zangrilli D, Mencarelli A, Diverio D, Biondi A, Lo Coco F, Rambaldi A, Grignani F. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J 11: , )Chen SJ, Chen Z, Chen A, Tong JH, Dong S, Wang ZY, Waxman S, Zelent A. Occurrence of distinct PML-RAR-alpha fusion gene isoforms in patients with acute promyelocytic leukemia detected by reverse transcriptase/polymerase chain reaction. Oncogene 7: , ) Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 57: , ) Chomienne C, Ballerini P, Balitrand N, Daniel MT, Fenaux P, Castaigne S, Degos L. All-trans retinoic acid in acute promyelocytic leukemias: II. in vitro studies: structure-function relationship. Blood 76: , ) Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, Lanotte M, Berger R, Chambon P. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J 11: , ) Huang W, Sun GL, Li XS, Cao Q, Lu Y, Jang GS, Zhang FQ, Chai JR, Wang ZY, Waxman S. Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood 82: , ) Vahdat L, Maslak P, Miller WH Jr, Eardley A, Heller G, Scheinberg DA, Warrell RP Jr. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RARalpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 84: , ) Chou WC, Tang JL, Yao M, Liang YJ, Lee FY, Lin MT, Wang CH, Shen MC, Chen YC, Tien HF. Clinical and biological characteristics of acute promyelocytic leukemia in Taiwan: a high relapse rate in patients with high initial and peak white blood cell counts during all-trans retinoic acid treatment. Leukemia 11: , ) Gallagher RE, Willman CL, Slack JL, Andersen JW, Li YP, Viswanatha D, Bloomfield CD, Appelbaum FR, Schiffer CA, Tallman MS, Wiernik PH. Association of PML-RAR alpha fusion mrna type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood 90: , ) Stock W, Moser B, Sher DA, Schachter-Tokarz E, Myers M, Powell BL, Bloomfield CD, Bucci D, Tallman MS, Larson RA, Gallagher RE. PML-RARα isoform at diagnosis is associated with disease-free survival in patients enrolled in the intergroup trial (C-9710) for treatment of Acute Promyelocytic Leukemia (APL). ASCO. Atlanta, U.S.: Journal of clinical oncology 338s, ) Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ. Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8: , ) Warrell RP Jr, Frankel SR, Miller WH Jr, Scheinberg DA, Itri

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy