Christina A. Ortmann, M.D., David G. Kent, Ph.D., Jyoti Nangalia, M.B.Chir., F.R.C.Path., Yvonne Silber, M.Sc.,David C. Wedge, Ph.D., Jacob Grinfeld, M.B. Effect of Mutation Order on Myeloproliferative Neoplasms R3. 박은지 / pf. 윤휘중 NEJM, February 12, 2015

Introduction Cancers - Accumulation of somatic mutations The phenotypic hallmarks of cancer, influence “ The order of mutation ” The myeloproliferative neoplasms - Chronic myeloid diseases - stem cells and progenitor cells from peripheral blood - → Clonal populations containing a sufficient number of cells - → Genotyping and phenotypic analysis Normal cell Cancer cell Gene mutation

Introduction - We have investigated the influence of mutation order in patients with myeloproliferative neoplasms that carry mutations in both JAK2 and TET2 - JAK2 and TET2 - Mutations in both genes are present in about 10% of patients with myeloproliferative neoplasms

Myeloproliferative disease (Total 246 patient) -Essential thrombocythemia (ET) : 92 -Polycythemia vera (PV) : 107 -Myelofibrosis (MF) : 47 Diagnosis The British Committee for Standards in Haematology Hematopoietic colony BFU-E (Burst forming unit – erythrocyte) CFU-E (Colony forming unit – erythrocyte) Methods Sanger sequencing pph. Blood mononulear cell BFU-E CFU-E EPO Mitosis Cytokines

Result (1) Non mutant TET2/JAK2 Essential thrombocythemiaPolycythemia veraMyelofibrosis No. of coloniesNo. of patients “ The order of muation → clinical features ”

Result (2) 1~23~4 “ Myelofibrosis is more advanced disease ”

Result (3) Total 24

Result (4) JJ, TJJ, JJT TJJ : 1.4%JJ or JJT : 57%

Result (5) GMP: Granulocyte macrophage progenitor MEP: Megakaryocyte erythroid progenitor CMP: Common myeloid progenitor cell CMP ↑ MET ↑ “ The order of mutation influences the types of progenitor cells”

Result (6) TJ or TJJ J or JJ

Result (7) yrs 60.7 yrs ETPV

Result (8) MI, CVA, Portal vein thrombosis, Splanic vein thrombosis, DVT, calf vein thrombosis … “ The order of mutation influences the thrombosis”

Conclusion The order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms

Thank you !