Rumi Elisa, Passamonti Francesco, Pietra Daniela, Della Porta Matteo G, Arcaini Luca, Boggi Sabrina, Elena Chiara, Boveri Emanuela, Pascutto Cristiana, Lazzarino Mario, Cazzola Mario
Department of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo and University of Pavia School of Medicine, Pavia, Italy.
Cancer. 2006 Nov 1;107(9):2206-11. doi: 10.1002/cncr.22240.
A somatic gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been identified in chronic myeloproliferative disorders, which appear to have a sporadic occurrence in most individuals. The authors studied the biologic significance of the JAK2 (V617F) mutation in familial myeloproliferative disorders.
Twenty pedigrees with familial chronic myeloproliferative disorders were identified through an investigation of family history in 264 patients with sporadic myeloproliferative disorders. A quantitative real-time polymerase chain reaction (qRT-PCR)-based allelic discrimination assay was employed for the detection of the V617F mutation in circulating granulocytes and T lymphocytes. An analysis of X-chromosome inactivation pattern was performed in female patients.
Fourteen families had homogeneous phenotypes, and 6 families had mixed phenotypes. By using a qRT-PCR-based allelic discrimination assay, the JAK2 (V617F) mutation was detected in circulating granulocytes from 20 of 31 patients, but the mutation was not detected in T lymphocytes. Granulocyte mutant alleles ranged from 2.1% to 91.5% and, on average, increased with time. Discordant distribution of the JAK2 (V617F) mutation was observed in siblings with polycythemia vera. The proportion of granulocytes that carried the JAK2 (V617F) mutation was lower than the proportion of clonal granulocytes, as determined in an analysis of X-chromosome inactivation patterns in female patients.
The current findings indicated that the JAK2 (V617F) mutation represents an acquired somatic mutation in patients with familial chronic myeloproliferative disorders and probably occurs as a secondary genetic event in the background of preexisting clonal hematopoiesis. Thus, a genetic predisposition to acquisition of JAK2 (V617F) is inherited in families with myeloproliferative disorders.
在慢性骨髓增殖性疾病中已鉴定出Janus激酶2（JAK2）基因的体细胞功能获得性突变，在大多数个体中这些疾病似乎为散发性。作者研究了JAK2（V617F）突变在家族性骨髓增殖性疾病中的生物学意义。
通过对264例散发性骨髓增殖性疾病患者的家族史进行调查，确定了20个患有家族性慢性骨髓增殖性疾病的家系。采用基于定量实时聚合酶链反应（qRT-PCR）的等位基因鉴别分析方法检测循环粒细胞和T淋巴细胞中的V617F突变。对女性患者进行了X染色体失活模式分析。
14个家系具有均一的表型，6个家系具有混合表型。通过基于qRT-PCR的等位基因鉴别分析，在31例患者中的20例循环粒细胞中检测到JAK2（V617F）突变，但在T淋巴细胞中未检测到该突变。粒细胞突变等位基因范围为2.1%至91.5%，且平均随时间增加。在真性红细胞增多症的同胞中观察到JAK2（V617F）突变的不一致分布。在女性患者的X染色体失活模式分析中确定，携带JAK2（V617F）突变的粒细胞比例低于克隆性粒细胞比例。
目前的研究结果表明，JAK2（V617F）突变代表家族性慢性骨髓增殖性疾病患者的获得性体细胞突变，可能作为继发遗传事件发生在已存在的克隆性造血背景中。因此，骨髓增殖性疾病家族中存在获得JAK2（V617F）的遗传易感性。
