title: Genetic-pathologic characterization of myeloproliferative neoplasms.
abstract: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic-pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome.
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yonggoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Joonhong
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Irene
authors.initials: I
authors.lastname: Jo
authors.affiliation: Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Gun Dong
authors.initials: GD
authors.lastname: Lee
authors.affiliation: Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ahlm
authors.initials: A
authors.lastname: Kwon
authors.affiliation: Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hayoung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Woori
authors.initials: W
authors.lastname: Jang
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Chae
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Kyungja
authors.initials: K
authors.lastname: Han
authors.affiliation: Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Leukemia Research Institute, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ki-Seong
authors.initials: KS
authors.lastname: Eom
authors.affiliation: Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Leukemia Research Institute, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Byung-Sik
authors.initials: BS
authors.lastname: Cho
authors.affiliation: Division of Hematology, Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Leukemia Research Institute, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Yeouido St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hwan
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hyunjung
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Uijeongbu St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Yoon Ho
authors.initials: YH
authors.lastname: Ko
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Haeil
authors.initials: H
authors.lastname: Park
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Bucheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jong Youl
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seungok
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Jekarl
authors.affiliation: Department of Hematology, Incheon St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yahng
authors.affiliation: Department of Laboratory Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Catholic Genetic Laboratory Center, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Myungshin
authors.initials: M
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D037282:Calreticulin / Q000235:genetics; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology*; D055728:Primary Myelofibrosis / Q000235:genetics / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics; D055815:Young Adult
chemical_list: C576483:CALR protein, human; D037282:Calreticulin; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2