Papadopoulos Nicolas, Nédélec Audrey, Rahmani Yacine, Ryou Hosuk, Defour Jean-Philippe, Rittscher Jens, Royston Daniel, Constantinescu Stefan N
de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.
Ludwig Institute for Cancer Research, Brussels, Belgium.
Blood. 2025 Jul 24;146(4):482-495. doi: 10.1182/blood.2024026711.
The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling through several type I cytokine receptors, namely the erythropoietin receptor, the thrombopoietin receptor (TpoR)/myeloproliferative leukemia (Mpl) protein, and the granulocyte colony-stimulating factor receptor. Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/Mpl absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, in which regulation of Jak2 expression does not depend on its natural promoter. In this study, we use a novel mouse model expressing Jak2 V617F under its endogenous promoter at the heterozygous state within a Mpl knockout background. Our findings indicate that erythrocytosis, leukocytosis, and moderate splenomegaly with mild perivascular fibrosis of the spleen persist even in the absence of Mpl expression. Notably, the inherent growth-stimulating effect induced by Jak2 V617F remains consistent across diverse early hematopoietic progenitor populations in the absence of Mpl but is reduced at the stem cell level and does not allow clonal expansion in competitive transplantation. Our results delineate Mpl-dependent and -independent phenotypes induced by Jak2 V617F and confirm that inhibiting Mpl expression at the stem cell level negates the long-term advantage of the mutant clone. Consequently, although Mpl emerges as a major player in Jak2 V617F-positive MPNs, our study underscores that it is not the exclusive contributor, broadening the spectrum for therapeutic intervention.
Jak2 V617F突变通过持续激活几种I型细胞因子受体的信号传导，成为骨髓增殖性肿瘤（MPN）的主要驱动因素，这些受体包括促红细胞生成素受体、血小板生成素受体（TpoR）/骨髓增殖性白血病（Mpl）蛋白和粒细胞集落刺激因子受体。其中，TpoR在造血干细胞的更新和分化中起关键作用，与突变的Jak2一起被定位为MPN的关键驱动因素。然而，仅通过转基因Jak2 V617F小鼠模型探索了在体内Jak2 V617F背景下TpoR/Mpl缺失的影响，在该模型中Jak2表达的调节不依赖于其天然启动子。在本研究中，我们使用了一种新型小鼠模型，该模型在Mpl基因敲除背景下，以杂合状态在其内源启动子下表达Jak2 V617F。我们的研究结果表明，即使在没有Mpl表达的情况下，红细胞增多、白细胞增多以及伴有脾脏轻度血管周围纤维化的中度脾肿大仍然存在。值得注意的是，在没有Mpl的情况下，Jak2 V617F诱导的内在生长刺激作用在不同的早期造血祖细胞群体中保持一致，但在干细胞水平上有所降低，并且在竞争性移植中不允许克隆扩增。我们的结果描绘了Jak2 V617F诱导的依赖Mpl和不依赖Mpl的表型，并证实抑制干细胞水平的Mpl表达会消除突变克隆的长期优势。因此，尽管Mpl是Jak2 V617F阳性MPN的主要参与者，但我们的研究强调它不是唯一的促成因素，拓宽了治疗干预的范围。
