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1 대한내과학회지 : 제 76 권제 2 호 2009 특집 (Special Review) - 골수이형성증의병태생리, 진단과치료 골수형성이상증후군의병태생리와감별진단 전남대학교의과대학내과학교실 김여경 김형준 Myelodysplastic syndrome: pathophysiology and differential diagnosis Yeo-Kyeoung Kim, M.D. and Hyeoung-Joon Kim, M.D. Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea Myelodysplastic syndrome (MDS) refers to a group of clonal disorders affect both hematopoietic stem cells and progenitor cells within the erythrocytic, granulocytic, and megakaryocytic lineages. Ineffective hematopoiesis, the major manifestation of MDS, arises from a complex interaction between hematopoietic progenitors and the microenvironment, resulting in premature apoptotic death of progenitors and their maturing progeny. Development and progression of MDS is suggested to be a multistep alteration to hematopoietic stem cells. Although the molecular pathogenesis of MDS has not been clearly elucidated, a model of MDS pathogenesis has been proposed whereby a normal hematopoietic stem cell acquires successive genetic abnormalities that ultimately lead to malignant transformation and clonal expansion. Early mutations in stem cells may cause differentiation arrest and apoptosis leading to dysplasia and cytopenia, wherease subsequent defects affecting myeloid cell proliferation may cause the clonal expansion of aberrant cells and leukemic transformation. The heterogeneity in the clinical and morphologic features in MDS reflects the diversity and complexity of the underlying genetic defects. Some of these different molecular alterations have been described. However, since the developing targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, it may be required to make further progress in understanding the exact pathomechanisms of this disease. (Korean J Med 76: , 2009) Key Words: Myelodysplastic syndrome; Pathophysiology; Diagnosis 서론골수형성이상증후군 (myelodysplastic syndrome; MDS) 은말초혈액내혈구감소증, 골수조혈세포계의형성이상 (dysplasia) 및무효조혈 (ineffective hematopoiesis) 을특징으로하는클론성질환으로, 수년간에걸쳐서서히진행하거나혹은급속하게급성백혈병으로진행하는등다양한임상경과를보인다 1). 이는다양한임상적, 형태학적, 생물학적, 그리고유전적인특징을가지는질환군이므로정확한진단과분류를시행하여각환자에맞는치료방침을결정하는것이매우중요하다. 최근골수형성이상증후군의발생및질환의 진행에관한다양한기전들이발견됨으로써이를기반으로조혈모세포이식외에도여러치료법들이시도되고있다. 이글에서는현재까지알려진골수형성이상증후군의발생및진행에관련된기전과감별진단에대해알아보고자한다. 골수형성이상증후군의원인및병태생리골수형성이상증후군의원인및발생기전은아직확실히규명되지않았으나, 조혈모세포의성숙이상과함께증식에이상을보이는클론성질환이다. 현재까지알려진골수형성이상증후군의원인으로는허용기준치이상의벤젠등유기용매에의노출, 흡연및혈액암의가족력등이보고되었으며, Fanconi

2 - The Korean Journal of Medicine: Vol. 76, No. 2, 빈혈, 선천성각화부전증 (dyskeratosis congenita), Shwachmann- Diamond 증후군및 Diamond-Blackfan 증후군등이골수형성이상증후군의발생율을높이는것으로알려져있다 2). 골수형성이상증후군은여러단계의병리기전을거쳐발병하게되는데 3, 4), 첫번째단계에서는화학물질, 방사선, 세포독성약물혹은유전자변이등에의해조혈모세포에유전적이상이일어나게되며, 이러한이상들이축적되면서세포주기조절, 종양억제유전자의전사등에영향을줌으로써골수형성이상증후군클론의팽창을가져온다. 초기에는골수의세포충실도가증가하나말초혈액의혈구세포는감소하는무효조혈이나타나는데, 이는골수내조혈모세포기원세포 (hematopoietic progenitor cell) 및분화된세포의고사 (apoptosis) 에의한것이다. 진행기에백혈병으로의이행은종양억제유전자 / 종양촉진유전자의변이혹은이러한유전자들의과메틸화등에의해발생하며이때에는세포고사가점진적으로감소하고미성숙세포의증식이나타나게된다. 1. 분자생물학적이상다양한종양촉진 / 종양억제유전자및정상조혈과정을조절하는유전자들의변이가골수형성이상증후군의분자생물학적병리기전에관여하는것으로알려져있다. 그러나대부분은질병의진행과연관되어있으며, 직접적으로골수형성이상증후군의발병에관여하는유전자는아직확실치밝혀져있지않다. 따라서질환의발병에직접적으로관련된유전자이상을규명하는것이앞으로의치료제개발에매우중요할것으로생각된다. 1) 신호전달계이상약 10~15% 의골수형성이상증후군환자에서 RAS 유전자변이가관찰되며주로 N-RAS 변이가가장많다. 이중점돌연변이가 12, 13 및 61번유전부호 (codon) 에서주로나타난다. RAS 단백주기는 guanosine triphosphate (GTP) 가결합된상태에서활성화되며, Raf 및 mitogen-activated protein kinase (MAPK) 를자극하여세포분화와증식에중요한 NF-IL6, ELK-1, c-jun 및 c-myc 등의전사인자를활성화시킨다. 이러한과정은 RAS에결합된 GTP가가수분해되면서억제되는데, 골수형성이상증후군에서관찰되는유전자의점돌연변이가발생하면 RAS-GTP의가수분해가차단되어 RAS의체질적활성화가유도된다. 이러한 N-RAS 돌연변이가있는골수형성이상증후군환자들은불량한예후를보이는것으로알려져있다 5, 6). Janus tyrosine kinase는싸이토카인관련유전자발현및세포분화에관련된것으로잘알려져있다. 이중 JAK2 V617F 변이가있는경우 kinase에의한지속적인인산화가일어남으로써골수증식성종양 (myeloproliferative neoplasm; MPN) 의발생이일어난다 7). 골수증식성종양과달리골수형성이상증후군에서는 JAK2 V617F 변이가 5% 정도에서만관찰되나, MDS/MPN 범주에속하는심한혈소판증가증을보이는환상철적모구불응성빈혈 (refractory anemia with ringed sideroblasts and thrombocytosis; RARS-T) 에서는 60% 이상에서이변이가발현되는것으로보고되었다 8, 9). 그러므로 RARS 환자들중혈소판치가증가되어있는환자들에서는 JAK2 유전자의변이를확인하여야한다. FLT3 유전자는 tyrosine kinase receptor를부호화하며조혈세포의증식, 분화및세포고사와관련된것으로알려져있다. 25~30% 의급성골수성백혈병에서 FLT3 유전자변이가관찰되는것에반해골수형성이상증후군에서는약 5% 의환자에서만이러한변이가나타나는데, 이러한 FLT3 유전자변이가나타난골수형성이상증후군환자들은급성골수성백혈병으로의이행율이높다 6, 10). 또한골수형성이상증후군의초기보다진행기에 FLT3 변이가증가하는것으로나타나 11), 이러한 FLT3의변이는골수형성이상증후군의발생보다는골수형성이상증후군으로부터급성백혈병으로의이행에관련된것으로생각된다. 2) 유전자전사인자및세포주기조절의이상 AML1 (CBFA2, PEBP2α, RUNX1) 유전자는모든조혈계세포에서발현되어조혈세포의발현에관련된다양한유전자의발현을조절한다 12). AML1/RUNX1의돌연변이는골수형성이상증후군에서비교적흔히관찰되며특히진행된골수형성이상증후군에서는 10~60% 까지관찰된다. AML/RUNX1 변이는 7번염색체이상과연관성이깊고, 백혈병으로의이행율이높다 13). p53 종양억제유전자는세포주기조절, 세포사멸및게놈안전성유지에관여하는데, 골수형성이상증후군환자의 10% 에서이유전자의변이가발견된다 14). 주로하나의대립유전자 (allele) 의과오돌연변이 (missense mutation) 와함께다른대립유전자의소실이발생하는경우가많다. 이러한 p53 변이는골수형성이상증후군고위험군에서주로관찰되며, 일반적으로복합적핵형을동반하여불량한예후를보인다 6). 유전자표현의개체신생적변성 (epigenetic alteration) 를초래하는주요기전중하나는 DNA 메틸화및히스톤비아세

3 - Yeo-Kyeoung Kim, et al. Myelodysplastic syndrome: pathophysiology and differential diagnosis - 틸화이다. DNA 메틸화는조혈모세포의염색질구조및전사제어에영향을미친다. 잘알려진바와같이종양억제유전자의유전자촉진부에 CpG island가 DNA methyltransferase 에의해과메틸화가일어나면염색질구조의변화및전사가억제되어종양억제유전자의발현이억제된다 15). 고위험군골수형성이상증후군에서는조혈모세포의세포주기조절및세포고사에관련된여러유전자의과메틸화가일어나는데, 대표적으로과메틸화가발견되는유전자는 p14 INK4B 로약 50% 의골수형성이상증후군환자에서발견되고있다 16, 17). 그외골수형성이상증후군에서과메틸화가발견된유전자로는 cancer 1 (HIC1), E-cadherin (CDH1), calcitonin, estrogen receptor (ER), cyclin-dependent kinase inhibitor genes p15, p16, p21 및 p57 등이다. 이러한유전자의과메틸화는불량한예후와관련이있다 18). 최근연구에서는적혈구계, 과립구계및혈소판계각각의조혈모세포계열별로특정유전자의과메틸화가나타났으며, 이로인해골수형성이상증후군의여러표현형이나타나고서로다른질환의경과를보임이확인되었다 19). 유전자변이와달리개체신생적변성은가역적인과정으로, 최근 5-azacytidine 혹은 5-aza-2'-deoxycitidine (decitabine) 과같은 DNA 저메틸화약제가골수형성이상증후군환자의치료에도입되어사용되고있다 20, 21). Histone acetyl transferase (HATs) 에의해뉴클레오솜히스톤의아세틸화가일어나면뉴클레오솜의구조가변화하면서전사가일어나게된다. 반대로 histone deacetylases (HDAC) 에의해히스톤으로부터아세틸기가제거되면염색질이안정화되어유전자의발현이억제된다 22). 일부연구에서는이러한 HDAC 억제제인 valproic acid를골수형성이상증후군환자에서사용함으로써유의한치료효과를얻었음을보고하였다 23). 또한이러한 DNA 메틸화와히스톤아세틸화는서로밀접하게연관이되어있으므로, 골수형성이상증후군환자에서 valproic acid와같은 HDAC 억제제와 DNA 저메틸화약제를병합하여시도가이루어지고있다 24). 3) 골수미세환경의이상골수기질세포는골수미세환경으로조혈과정에영향을미친다. 일부연구에서는골수형성이상증후군환자의골수기질세포에서특징적인염색체이상및싸이토카인의변화가나타났다 25, 26). 그러나골수형성이상증후군에서골수기질세포가악성클론으로부터유도되는지혹은질환의진행에영향을미치는지에대해서는좀더연구가필요하다. 고형암에서와마찬가지로골수형성이상증후군의발생및 진행에있어서도혈관생성의변화가중요한역할을할것으로생각되고있다. 일부연구에서는골수형성이상증후군환자의골수조직은정상인에비해혈관분포도가증가되었으며, 혈장의혈관내피성장인자 (vascular endothelial growth factor, VEGF), basic fibroblast growth factor 및 hepatocyte growth factor 등의농도역시증가함을보고하였다 27). 이러한미세혈관의증식은골수형성이상증후군의초기에주로관찰되어초기골수형성이상증후군에서 lenalidomide 혹은 VEGF 억제제의사용이효과가있을것으로생각된다 28, 29). 골수형성이상증후군의분류및감별진단골수형성이상증후군은과거다섯가지로분류되었던 FAB 분류법으로부터 1999년세계보건기구 (WHO) 분류법에의해여덟가지형태로분류되었다. 최근이 WHO 분류법이새로이개정되어발표되었는데 ( 표 1) 30), 기존분류와비교하였을때 2008년에새로생긴진단군으로는 refractory cytopenia with unilineage dysplasia (RCUD) 로빈혈, 호중구감소증및혈소판감소증을각각정의하였다. 혼합된골수형성이상 / 골수증식성종양 (mixed myelodysplastic/myeloproliferative neoplasms, MDS/MPN) 의범주에는기존분류에서와같이만성골수단구성백혈병 (chronic myelomonocytic leukemia, CMML), 비정형만성골수성백혈병 (atypical chronic myeloid leukemia, acml), 연소기골수단구성백혈병 (Juvenile myelomonocytic leukemia, JMML), 미분류골수형성이상 / 골수증식종양 (MDS/ MPN, unclassifiable) 로나뉘었고, 새로이심한혈소판증가증을보이는 RARS-T가추가되었다 30). 골수형성이상증후군을진단하고분류하기위해서는골수나말초혈액내모세포의존재, 형성이상의정도및환상철적모구의존재를확인해야한다. 말초혈액혈구감소증은각조혈계의이형성정도와대부분일치하나일부에서는불일치를보이는경우도있다 31). 골수내형성이상과모세포의백분율측정하기위해서는최소 500개이상의골수내유핵세포를확인하여야하며, 적어도하나의조혈모세포계열에서 10% 이상의형성이상이발견되어야의미있는형성이상으로생각할수있다. 대표적인형성이상소견으로는다핵세포나핵분절의존재, 거대적혈모구양변화, 세포질이상, 공포함유, PAS 양성소견, 환상철적모세포의존재, 적혈모구의증가, 소형거대핵세포또는대형단일핵거대핵세포의존재등이다. 모세포의백분율을측정한뒤 5% 미만, 5~9 %, 및 10 ~19% 의세군으로나누며, 적혈구계전구세포가전체골수세포의 50% 이상을차지하고있는경우에는적혈구계전구

4 - 대한내과학회지 : 제 76 권제 2 호통권제 582 호 Table 1. Updated WHO classification of myelodysplastic syndrome (2008) Disease Blood findings Bone marrow findings Refractory cytopenias with unilineage dysplasia (RCUD) Refractory anemia (RA): Refractory neutropenia (RN), Refractory thrombocytoepnia (RT) Refractory anemia with ring sideroblasts (RARS) Refreactory cytoepnia with multilineage dysplasia (RCMD) Refractory anemia with excess blasts-1 (RAEB-1) Refractory anemia with excess blasts-2 (RAEB-2) Unicytopenia or bicytopenia * No or rare blasts (<1%) Anemia, No blasts Cytopenia (s) No or rare blasts (<1%) <1x 109/L monocytes Cytopenia (s) <1x 109/L monocytes Cytopenia (s) 5-19% blasts Auer rods± <1x 109/L monocytes Unilineage dysplasia: 10% of the cells in one myeloid lineage <15% of erythroid precursors are ring sideroblasts 15% of erythroid precursors are ring sideroblasts Erythroid dysplasia only Dysplasia in 10% of the cells in two myeloid lineages (neutrophil and/or erythroid precursors and /or megakaryocytes) in marrow ±15% ring sideroblasts Unilineage or multileneage dysplasia 5~9% blasts Unilineage or multileneage dysplasia 10~19% blasts Auer rods± Myelodysplastic syndrome-unclassified (MDS-U) Cytopenias Unequivocal dysplasia in less than 10% of cells in one 1% blasts or more myeloid cell lines when accompanied by a cytogenetic abnormality considerred as presumptive evidence for a diagnosis of MDS MDS associated with isolated del(5q) Anemia Usually normal or increased platelet counts No or rare blasts (<1%) Normal to increased megakaryocytes with hypolobated nuclei Isolated del (5q) cytogenetic abnormality * Bicytoepnia may occasionally be observed. Cases with pancytopenia should be classified as MDS-U. If the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic classification in RAEB-1. Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as MDS-U. Cases with Auer rods and <5% myeloblasts in the blood and <10% in the marrow should be classified as RAEB-2. 세포를제외한나머지골수세포중에서모세포의백분율을계산한다 30). 골수형성이상의정도를결정하기위해서는골수검체의슬라이드제작시도말및염색기법이중요하다. 가능하면채취후 2시간이내의신선검체로항응고제가첨가되지않 은검체를이용하여확인하는것이좋다. 또한생검조직은적어도 1~2 cm 크기로채취하며, 겉질뼈 (cortical bone) 바로하방의골수세포충실도는안쪽보다낮게나오는경우가많아반드시이부분을통과하여내부충실도를볼수있도록채취하여야재생불량성빈혈로오진하는것을막을수있다 30)

5 - 김여경외 1 인. 골수형성이상증후군의병태생리와감별진단 - 세포유전학적검사를시행하여염색체이상을확인하는것이골수형성이상증후군의진단및예후결정에매우중요하다. 형태학적이상만으로골수형성이상증후군을확진하기어려울때이러한핵형이상을확인하는경우확진이가능하다. 이러한세포유전학적검사는진단시뿐만아니라진단후에말초혈액소견의변화로인해골수검사를재시행할때마다반복시행하여염색체이상의변화유무를확인하여야한다. 전술한바와같이특정염색체이상은예후에영향을주며특별한형태학적이상과연관되어있기도한다. 5q 결손시에는거대핵세포의분엽수가적어지거나없어지며, 17q 결손시에는저엽성호중구가출현할수있다 30). 그러나골수조혈세포의형성이상이반드시클론성질환이라는증거는되지않는다. 그러므로진단전이차적으로골수형성이상을유발할수있는다른원인들에대한확인이반드시필요하다. 대표적으로비타민 B12 혹은엽산결핍등영양소결핍, 비소, 알코올등의독성물질노출, 항암제및조혈촉진인자등의치료병력, HIV, parovovirus B19 등의감염및선천성적혈구이형성빈혈혹은발작성야간혈색소뇨증등을감별하여야한다. 대부분의골수형성이상증후군환자에서골수세포충실도는정상혹은증가를보이나, 10~20% 의환자에서는골수세포충실도가나이에비해감소하는경향을보여 (60세미만환자 : <30%, 60세이상환자 : <20%) 재생불량성빈혈과의감별이문제가된다. 골수도말검사상과립구나거대핵세포의형성이상이관찰되는경우는골수형성이상증후군으로진단할수있으나, 적혈구계의형성이상은재생불량성빈혈에서도나타날수있다. 반면에 CD34+ 세포분획이정상이거나증가한경우혹은세포유전학검사상염색체이상이발견된경우는재생불량성빈혈보다골수형성이상증후군을생각할수있다 32). 또한처음부터진단이어려운경우에는수개월간의간격을두고반복적으로세포유전학검사를포함하여골수생검을추적하여시행하도록한다 30). 결론골수형성이상증후군은조혈모세포및그전구세포를침범하는클론성질환군으로주된특징중의하나인무효조혈은조혈계전구세포와미세환경간의다양한상호작용으로인해골수내조혈모세포및그기원세포의고사로인해발생한다. 골수형성이상증후군의발생및급성백혈병으로의진행은여러단계에걸친조혈모세포의변이에의한것으로, 현재까지는그기전이모두밝혀지지는않았으나초기 에는다양한원인에의한유전적변이에의해세포분화의억제및세포고사가일어나형성이상및혈구감소를나타내며, 진행기에는이상세포의클론성증식및백혈병으로의진행이나타난다. 골수형성이상증후군의형태및임상경과가매우다양한것으로미루어볼때질환을일으키는유전적이상이다양할것으로생각되며, 일부분자생물학적이상은이미알려져있다. 그러나골수형성이상증후군의표적치료를위해서는질환의발생및진행에관련된기전을명확하게밝히는것이중요하므로이에대한추가연구가필요할것으로사료된다. 중심단어 : 골수형성이상증후군 ; 병태생리 ; 진단 REFERENCES 1) Kröger N. Epigenetic Modulation and Other Options to Improve Outcome of Stem Cell Transplantation in MDS. Hematology Am Soc Hematol Educ Program 2008:60-67, ) Strom SS, Gu Y, Gruschkus SK, Pierce SA, Estey EH. Risk factors of myelodysplastic syndromes: a case-control study. Leukemia 19: , ) Nimer SD. MDS: A Stem Cell Disorder-But What Exactly Is Wrong with the Primitive Hematopoietic Cells in This Disease? Hematology Am Soc Hematol Educ Program 2008: 43-51, ) Nolte F, Hofmann WK. Myelodysplastic syndromes: molecular pathogenesis and genomic changes. Ann Hematol 87: , ) Beaupre DM, Kurzrock R. RAS and leukemia: from basic mechanisms to gene-directed therapy J Clin Oncol 17: , ) Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia 12: , ) James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434: , ) Renneville A, Quesnel B, Charpentier A, Terriou L, Crinquette A, Laï JL, Cossement C, Lionne-Huyghe P, Rose C, Bauters F, Preudhomme C. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia 20: , ) Szpurka H, Tiu R, Murugesan G, Aboudola S, Hsi ED, Theil KS, Sekeres MA, Maciejewski JP. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis

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7.Æ¯Áýb71ÎÀ¯È« š J KMA Special Issue Myelodysplastic Syndrome June Won Cheong, MD Yoo Hong Min, MD Department of Internal Medicine, Yonsei University College of Medicine E mail : jwcheong70@yumc.yonsei.ac.kr minbrmmd@yumc.yonsei.ac.kr