Kim Yonggoo, Park Joonhong, Jo Irene, Lee Gun Dong, Kim Jiyeon, Kwon Ahlm, Choi Hayoung, Jang Woori, Chae Hyojin, Han Kyungja, Eom Ki-Seong, Cho Byung-Sik, Lee Sung-Eun, Yang Jinyoung, Shin Seung-Hwan, Kim Hyunjung, Ko Yoon Ho, Park Haeil, Jin Jong Youl, Lee Seungok, Jekarl Dong Wook, Yahng Seung-Ah, Kim Myungshin
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.
Exp Mol Med. 2016 Jul 22;48(7):e247. doi: 10.1038/emm.2016.55.
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.
骨髓增殖性肿瘤（MPNs）是一类克隆性造血干细胞疾病，其特征为一个或多个髓系谱系的增殖。当前研究表明，在407例MPNs患者中，82.6%检测到三种驱动突变，其中JAK2突变275例（67.6%），CALR突变55例（13.5%），MPL突变6例（1.5%）。原则上这些突变相互排斥，但有1例患者同时存在CALR和MPL突变。驱动突变决定了MPNs的病理特征，包括谱系增生、实验室检查结果及临床表现。JAK2突变的MPN表现为红系、粒系和/或巨核系增生，而CALR和MPL突变的MPNs表现为粒系和/或巨核系增生。谱系增生与较高的突变等位基因负担及外周血细胞增多密切相关。这些发现证实，谱系增生由获得驱动突变的各造血谱系的克隆性增殖组成。我们的研究还表明，骨髓（BM）纤维化与疾病进展相关。明显纤维化（≥2级）的患者突变等位基因负担增加（P<0.001），染色体异常增加（P<0.001），预后较差（P<0.001）。此外，在明显纤维化的患者中，所有野生型JAK2/CALR/MPL（三阴性）患者经全基因组微阵列研究均显示基因组改变，且总生存期最差，其次是JAK2突变的MPNs。遗传病理特征为理解MPNs的疾病发病机制及进展提供了信息。驱动突变和BM纤维化的预后意义提示有必要采取前瞻性治疗策略以改善临床结局。
