Targeting the CALR interactome in myeloproliferative neoplasms
Targeting the CALR interactome in myeloproliferative neoplasms
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DOI：
10.1172/jci.insight.122703
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发表时间：
2018-11-15
期刊：
影响因子：
8
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
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作者：
Pronier, Elodie;Cifani, Paolo;Levine, Ross L.
ER 伴侣钙网蛋白 (CALR) 突变在骨髓增生性肿瘤 (MPN) 患者中很常见，可激活血小板生成素受体 (MPL)，并介导组成型 JAK/STAT 信号传导。 CALR 突变引起骨髓转化的机制尚未完全确定。我们使用质谱蛋白质组学来鉴定 CALR 突变相互作用蛋白。突变的 CALR 导致结合伴侣的错误定位，并增加 FLI1、ERP57 和 CALR 向 MPL 启动子的募集以增强转录。与 CALR 介导的 JAK/STAT 激活的关键作用一致，我们在体外和体内证实了 JAK2 抑制对 CALR 突变细胞的功效。由于 CALR 突变引起的相互作用组发生改变，我们假设 CALR 突变 MPN 可能容易受到异常 CALR 蛋白复合物的破坏。一种设计用于竞争性抑制 CALR 羧基末端的合成肽，可特异性消除细胞系和初级样品中的 MPL/JAK/STAT 信号传导，并提高 JAK 激酶抑制剂的功效。据我们所知，这些发现揭示了一种针对 CALR 突变 MPN 患者的新型潜在治疗方法。
Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57, and CALR to the MPL promoter to enhance transcription. Consistent with a critical role for CALR-mediated JAK/STAT activation, we confirmed the efficacy of JAK2 inhibition on CALR-mutant cells in vitro and in vivo. Due to the altered interactome induced by CALR mutations, we hypothesized that CALR-mutant MPNs may be vulnerable to disruption of aberrant CALR protein complexes. A synthetic peptide designed to competitively inhibit the carboxy terminal of CALR specifically abrogated MPL/JAK/STAT signaling in cell lines and primary samples and improved the efficacy of JAK kinase inhibitors. These findings reveal what to our knowledge is a novel potential therapeutic approach for patients with CALR-mutant MPN.