골수증식 질환 Myeloproliferative disorders (MPD) [ 새로운 분류와 진단 기준 ] 경희의대 종양혈액내과 조 경 삼

Myeloproliferative Disorders Clonal disorders of the hematopoietic stem cell Overproduction of mature, functional blood cells Long clinical course

History 1879 : HeuckIdiopathic myelofibrosis 1892 : Vaquez Polycythemia vera 1934 : EpsteinEssential thrombocythemia 1951 : DamesheckMyeloproliferative syndrome (CML, PV, ET, IMF) 2001 : WHO classification (CML, PV, ET, CIMF, CNL, CEL/HES, SM, CMPD-u) Dysregulated tyrosine kinases (Ph: bcr-abl) 2005 :JAK2V617F mutation

Myeolproliferative disorders Polycythemia vera (PV) : 40-50% survive about 10 years Essential thrombocythemia (ET) : 5 year survival of greater than 50% Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis Agnogenic myeloid metaplasia with myelofibrosis (AMM/MF) : median survival 3.5 – 5.5 years Chronic myelocytic leukemia (CML) : Ph(BCR-ABL)

Characteristics of CMPD Disease Hct WBC Platelet Splenomegaly LAP MF Ph or bcr/abl CML N or↓ ↑↑↑ ↑to↓ +++ ↓to 0 ± + PV ↑↑ ↑ ↑ + ↑↑ ± 0 ET N N ↑↑↑ + ↑or N ± 0 AMM/MF ↓ ↑to↓ ↑to↓ +++ ↑or N

Working Classification of Chronic Myeloid Disorders NEJM vol. 342:1255, 2000 (Harrison 15th Ed.)

WHO Classification of Myeloid Neoplasms Acute Myeloid Leukemia (AML) Myelodysplastic Syndromes (MDS) Myelodysplastic/myeloproliferative diseases (MDS/MPD) Myeloproliferative diseases (MPD)

WHO Classification of AML Acute myeloid leukemia with recurrent genetic abnormalities Acute myeloid leukemia with multilineage dysplasia Acute myeloid leukemia and myelodysplastic syndromes, therapy-related Acute myeloid leukemia, not otherwise categorized

WHO Classification(1) I. AML with recurrent cytogenetic translocation  AML with t(8;21)(q22;q22); AML1(CBFα)/ETO  APL [AML with t(15;17)(q22;q12) and variants; PML/RARα]  AML with abnormal bone marrow eosinophils [inv(16)(p13q22) or t(16;16)(p13;q22) CBFβ/MYH1]  AML with 11q23 (MLL) abnormalities

WHO Classification(2) II. AML with multilineage dysplasia  With prior myelodysplastic syndrome  Without prior myelodysplastic syndrome III. AML and myelodysplastic syndrome, therapy-related  Alkylating agent-related  Epipodophyllotoxin-related  Other types

WHO Classification(3) IV. AML not otherwise categorized  AML minimally differentiated  AML without maturation  AML with maturation  Acute myelomonocytic leukemia  Acute monocytic leukemia  Acute erythroid leukemia  Acute megakaryocytic leukemia  Acute basophilic leukemia  Acute panmyelosis with myelofibrosis  Myeloid sarcoma

WHO classification of MDS Refractory anemia (RA) RA with multilineage dysplasia (RCMD) RA with ringed sideroblasts (RARS) RCMD-RS RA with excess blasts-1 (RAEB-I) RAEB-II MDS, unclassified (MDS-U) MDS associated with isolated del(5q)

WHO classification of Myelodysplastic/myeloproliferative diseases Chronic myelomonocytic leukemia (CMML) Atypical chronic myeloid leukemia (aCML) Juvenile myelomonocytic leukemia (JMML) Myelodysplastic/myeloproliferative disease, unclassifiable (MDS/MPD, U)

WHO Classification of Myeloproliferative Diseases Chronic myelogenous leukemia, [Ph chromosome, t(9;22)(q34;q11), BCR/ABL-positive] Polycythemia vera Essential thrombocythemia Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis) Agnogenic myeloid metaplasia with myelofibrosis Chronic neutrophilic leukemia Chronic eosinophilic leukemia (and the hyperdosinophilic syndrome) Systemic mastocytosis Chronic myeloproliferative disease, unclassifiable

Molecular lesions associated with the MPD BCR-ABLCML (100%) JAK2 V617FPV (95%), ET(50-60%), IMF(50-60%), other myeloid disorders (1-5%) MPL W551K/LIMF (5%), ET(1%) KIT mutationsSM FIP1L1-PDGFRACEL PDGFRB fusion genes CMML(rare) FGFR fusion genes CMML(rare)

CML Philadelphia chromosome: t(9;22)(q34;q11) bcr-abl fusion gene : BCR/ABL mRNA Bcr/Abl fusion protein (p210 BCR-ABL ) normal abl gene: p145, tyrosine kinase Functional change Active tyrosine kinase : prevent apoptosis Attenuated DNA protein-binding activity Enhanced Abl binding to cytoskeletal actin

JAK2 tyrosine kinase mutation 2005 년 4 group in PV, ET, IMF JAK2V617F : exon 14 (1849G – T); 617valine – phenylalanine  PV : 95%  ET : 50 – 60%  IMF :50-60%  Other myeloid disorder :1-5% 2007 년 exon 12 mutation in PV and idiopathic erythrocytosis (NEJM 356:459)

JAK-STAT signaling by JAK2V617F Auto-phosphorylation Strong signaling

The JAK2 protein binds to multiple cytokine receptors

Gene dosage effects - almost all PV : homozygous mutations - ET : only heterozygous mutation or wild- type colonies  possibility of gene dosage effects to phenotype of cells  homozygous mutation towards erythroid proliferation and PV

Mitotic recombination of chromosome 9

Diagnostic criteria of MPD

PVSG diagnostic criteria for PV Category A  A1 : Increased red cell mass  M > 36 mL/kg  F > 32 mL/kg  A2 : Oxygen saturation > 92%  A3 : Splenomegaly Category B  B1 : Platelet > 400 X 10 9 /L  B2 : WBC > 12 X 10 9 /L  B3 : LAP score > 100  B4 : Serum B 12 > 900 pg/mL U B 12 > 2,200 pg/mL

The WHO criteria for the diagnosis of PV A1 : Elevated RCM (>25% more than mean normal predicted value, of Hb more than 185 g/L in male, 165 g/L in woman) A2 : No cause of SE A3 : Splenomegaly A4 : Clonal genetic abnormality other than Ph of BCR/ABL fusion gene in marrow cells A5 : Endogenous erythroid colony formation in vitro B1 : Thrombocytosis more than 400 x 10 9 /L B2 : WBC more than 12 x 10 9 /L B3 : Bone marrow biopsy showing panmyelosis with prominent erythroid and megakaryocytic proliferation B4 : Low Epo levels A1 + A2 + any other A A1 + A2 + 2 Bs

PRV-1 in neutrophil, c-MPL in megakaryocytes

Diagnosis of ET Markedly elevated platelet count in the absence of an identifiable cause of secondary thrombocytosis Diagnostic criteria  Platelet count persistently greater than 1 million per microliter in the absence of any identifiable cause  Normal red cell volume or Hb < 13 g/dL  Presence of iron in the BM  Absence of collagen fibrosis in the BM biopsy  Absence of Ph 1 chromosome

Diagnosis of IMF Bone marrow biopsy: essential May be difficult to distinguish from other CMPD Rule out other causes of myelofibrosis Acute myelofibrosis: M7 Myelodysplasia with myelofibrosis

New diagnostic criteria of MPD JAK2 mutation-positive JAK2 mutation-negative

PV

ET

IMF

PV

ET

IMF

JAK2 in MPD Diagnosis and classification Prognosis : thrombosis, survival Treatment : JAK2, JAK2-STAT