Circ0014614-miR9-3p轴上调MEPs中ITGB1的表达并诱导MSC成骨化促进ET形成和发展

近年来发生驱动基因突变的干祖细胞重塑的肿瘤niche参与MPN发生发展受到关注,但突变的HSCs重塑微环境的原因和机制知道甚少。我们前期研究表明ET患者MEPs外泌体装运circ0014614出现障碍,富集于MEPs胞浆中,负调控与其结合的miR9-3p,上调ITGB1引起MEPs的异常增殖及凋亡减少,扩增的MEPs影响MCSs的成骨化。基于此我们提出假说circ0014614-miR9-3p轴上调ITGB1引起MEPs异常扩增,重塑niche,诱导MCSs成骨化及OBCs的异常扩增,促进ET的形成和发展。为验证假说我们将体外调变miR9-3p及ITGB1,深入探讨circ0014614-miR9-3p-ITGB1调控通路异常的MEPs与niche中基质细胞“互话”的机制,并构建基因敲除的MPN小鼠进行体内验证。本研究对探索ET诊断和治疗的新靶点具有重要研究意义。

Recent years there is increasing attention on the involvement of tumor niche with the reconstruction of stem progenitor cells harboring driver mutations, into the development and progression of MPN. However, little is known about the reason and mechanism of the reconstruction of micro-environment by HSCs with gene mutations.Our previous study showed that circ0014614, which plays as exosomes shipment in megakaryocyte-erythroid progenitors (MEPs), was abnormal in the patients with essentialthrombocythemia (ET). Circ0014614 enriched in the plasma of MEPs, negatively regulated miR9-3p, which combines with circ0014614. Circ-0014614- miRNA9-3paxis induced abnormal proliferation and decreasing apoptosis of MEPs by up-regulation of β1-integrins (ITGB1). In turn,increasing MEPs influenced the ossification of MCSs and the amplification of OBCs. Based on those, we hypothesize that circ-0014614- miRNA9-3p axis reconstructs niche to boost the ossification of MCSs by up-regulation of ITGB1 to induce abnormal amplification of MEPs.In order to verify our hypothesis, we are going to regulate miR9-3p and ITGB1 in MEPs in vitro, furtherly explore the mechanism of cross-talk of abnormal regulation of circ0014614-miR9-3p-ITGB1 pathway with stroma cell in niche, and then do the verification in vivo by establishment of a MPN mouse model with gene knockout. Aim of this study is to reveal the mechanism of reconstruction of niche by stem progenitor cells harboring mutated genes in ET. It has a significance in exploring new therapy targets in ET.