Zimolova Veronika, Burocziova Monika, Berkova Linda, Grusanovic Srdjan, Gursky Jan, Janotka Lubos, Kasparek Petr, Pecinova Alena, Kundrat David, Hrckulak Dusan, Onhajzer Jakub, Jeziskova Ivana, Nekvindova Lucie, Weinbergerova Barbora, Pospisilova Sarka, Doubek Michael, Alberich-Jorda Meritxell, Korinek Vladimir, Divoky Vladimir, Lanikova Lucie
Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Laboratory of Hematooncology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
Leukemia. 2025 Aug 21. doi: 10.1038/s41375-025-02737-w.
The acquired JAK2-V617F mutation plays a causal role in myeloproliferative neoplasms (MPN). Weakly activating JAK2 germline variants have been associated with MPN risk, but the underlying mechanisms remain unclear. We previously identified the JAK2-R1063H germline variant, which contributes to hereditary MPN and increased disease severity in essential thrombocythemia. Here, we studied alterations in hematopoiesis in Jak2-R1063H knock-in mice. The Jak2-R1063H mouse cohort exhibited increased mortality, stimulated thrombopoiesis and elevated D-dimers levels, indicative of thrombotic complications. Bone marrow analysis revealed myeloid bias, enhanced megakaryopoiesis and activation of inflammatory signaling. Transcriptional and functional assays of hematopoietic stem cells suggested their accelerated aging and functional decline. The Egr1 transcriptional network, including the Thbs1 gene, progressively increased in aging mice, reinforcing alterations initiated by Jak2/Stat signaling. In murine acute myelogenous leukemia models, the Jak2-R1063H cooperated with a driver oncogene in promoting leukemogenesis. Germline JAK2-R1063H was found in 10 of 200 MPN patients from local hematology centers, with a higher minor allele frequency compared to healthy controls. Patients harboring JAK2-R1063H variant exhibited an increased incidence of thrombotic complications and disease progression with shortened survival. In conclusion, our findings identify the JAK2-R1063H germline variant as a risk factor for MPN development, thrombotic complications, and leukemic transformation. Our study, which involves a mouse model and a cohort of 200 MPN patients, characterizes the JAK2-R1063H germline mutation as a risk factor for MPN development, thrombotic complications, and leukemic transformation. These findings may have important clinical implications for managing MPN patients carrying the JAK2-R1063H germline variant.
获得性JAK2-V617F突变在骨髓增殖性肿瘤（MPN）中起因果作用。弱激活的JAK2种系变体与MPN风险相关，但其潜在机制仍不清楚。我们之前鉴定出JAK2-R1063H种系变体，它导致遗传性MPN并增加原发性血小板增多症的疾病严重程度。在此，我们研究了Jak2-R1063H基因敲入小鼠造血的改变。Jak2-R1063H小鼠队列表现出死亡率增加、血小板生成受刺激以及D-二聚体水平升高，提示有血栓形成并发症。骨髓分析显示髓系偏向、巨核细胞生成增强以及炎症信号激活。造血干细胞的转录和功能分析表明其加速衰老和功能衰退。包括Thbs1基因在内的Egr1转录网络在衰老小鼠中逐渐增加，强化了由Jak2/Stat信号引发的改变。在小鼠急性髓性白血病模型中，Jak2-R1063H与驱动癌基因协同促进白血病发生。在当地血液学中心的200例MPN患者中，有10例发现了种系JAK2-R1063H，与健康对照相比，其次要等位基因频率更高。携带JAK2-R1063H变体的患者血栓形成并发症和疾病进展的发生率增加，生存期缩短。总之，我们的研究结果确定JAK2-R1063H种系变体是MPN发生、血栓形成并发症和白血病转化的危险因素。我们涉及小鼠模型和200例MPN患者队列的研究将JAK2-R1063H种系突变表征为MPN发生、血栓形成并发症和白血病转化的危险因素。这些发现可能对管理携带JAK2-R1063H种系变体的MPN患者具有重要的临床意义。
