Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, USA.
Department of Pathology, SUNY Upstate Medical University, Syracuse, NY, USA.
Leukemia. 2014 Aug;28(8):1627-35. doi: 10.1038/leu.2014.52. Epub 2014 Jan 31.
JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p (9pLOH) involving the JAK2 locus has been observed in ∼30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have used conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F.
JAK2V617F 是费城染色体阴性骨髓增殖性肿瘤（MPN）中最常见的突变。虽然大多数 MPN 患者携带杂合 JAK2V617F 突变，但在约 30%的 MPN 患者中观察到涉及 JAK2 基因座的 9 号染色体短臂缺失（9pLOH）。JAK2V617F 纯合子通过 9pLOH 与更严重的 MPN 表型相关。然而，9pLOH 在 MPN 发病机制中的作用仍不清楚。为了研究野生型 JAK2（JAK2 WT）和 JAK2V617F 等位基因在 MPN 发病机制中的作用，我们使用了条件性 Jak2 敲除和 Jak2V617F 敲入小鼠，并生成了杂合子、半合子和纯合子 Jak2V617F 小鼠。虽然杂合子 Jak2V617F 表达导致小鼠出现类似真性红细胞增多症的 MPN，但在半合子或纯合子 Jak2V617F 小鼠中丢失 Jak2 WT 等位基因会导致外周血白细胞、中性粒细胞、网织红细胞和血小板显著增加，与杂合子 Jak2V617F 小鼠相比，脾脏明显增大。半合子或纯合子 Jak2V617F 小鼠还表现出比表达杂合子 Jak2V617F 的小鼠更快的骨髓纤维化。这些结果表明，Jak2 WT 等位基因的缺失增加了 MPN 的严重程度。因此，Jak2 WT 等位基因作为 Jak2V617F 诱导的 MPN 的负调节剂发挥作用。
