Division of Hematology & Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Department of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Am J Hematol. 2024 Jul;99(7):1220-1229. doi: 10.1002/ajh.27311. Epub 2024 Apr 17.
Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2 or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2 and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2 in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2 mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2 kinase. Similar to PV, the JAK2 native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2 PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2 gain-of-function mutation with many but not all comparable molecular features to JAK2 PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.
真性红细胞增多症（PV）是一种克隆性疾病，源于 JAK2 基因的获得性体细胞突变，包括 JAK2 或其他几个位于外显子 12 的突变。一位 38 岁的女性在 32 岁时中风，发现血红蛋白升高，白细胞正常，血小板正常，JAK2 和外显子 12 突变检测均为阴性。下一代测序显示了一种新的突变：位于假激酶结构域（JH2）的 JAK2 47.5%。其在指甲 DNA 中的存在证实了它的种系来源。她的母亲和儿子也有红细胞增多症和 JAK2 突变。计算机建模表明存在获得性功能的 JAK2 活性。先证者及其母亲有克隆性多能造血，排除了另一种源自体细胞突变的克隆性造血。三代人的一些红细胞祖细胞在没有促红细胞生成素的情况下生长，这是 PV 的一个标志。体外报告基因检测证实 JAK2 激酶活性增加。与 PV 相似，JAK2 原代细胞中 STAT5 磷酸化增加，促血栓形成和炎症基因的转录物增加，KLF2 转录物减少。先证者羟脲治疗无效，JAK2 抑制剂不耐受；然而，罗匹干扰素-α-2b（Ropeg-IFN-α）诱导缓解。Ropeg-IFN-α 治疗也降低了先证者、她的母亲和 JAK2 PV 患者的 JAK2 活性。我们报告了一种新的种系 JAK2 获得性功能突变引起的显性遗传性红细胞增多症，其具有许多但并非所有与 JAK2 PV 相当的分子特征。我们还记录了 Ropeg-IFN-α 对 JAK2 信号的一种以前未报道的抑制机制。
