Defining the cancer-specific proteome in Calreticulin-mutant myeloproliferative neoplasms

定义钙网蛋白突变型骨髓增生性肿瘤中的癌症特异性蛋白质组

• 批准号: 422428861
• 负责人: Dr. Jonas Samuel Jutzi
• 金额: --
• 依托单位: Division of Hematology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/422428861?language=en
• 关键词: Defining; cancer; specific; proteome; Calreticulin

Philadelphia-negative myeloproliferative neoplasms comprise a group of malignant hematological diseases. The genetic landscape of myeloproliferative neoplasms is very well described, with calreticulin being the second most common mutated gene after JAK2. Calreticulin mutations are found in up to 40% of patients with myeloproliferative neoplasms. Moreover, calreticulin and JAK2V617F mutations are mutually exclusive. All calreticulin mutations cluster in the last coding exon and result in deletion of the C-terminal “KDEL“ sequence, which normally retains wildtype calreticulin to the endoplasmic reticulum where it acts as a chaperone protein. The two most prominent mutations (Type I and II) both lead to frameshifts that generate a common mutant-specific 36-amino acid C-terminal peptide. In the new C-terminus, negatively charged amino acids are replaced by positively charged ones, mainly arginine and lysine. Recently, one mechanism by which mutant calreticulin is oncogenic has been delineated. Dr. Mullally’s lab showed that mutant calreticulin develops a pathogenic interaction with the thrombopoietin receptor, which activates the downstream signaling pathway in a thrombopoietin-independent manner. Moreover, it has been demonstrated that both the positive electrostatic charge of the mutant calreticulin C-terminus and the lectin binding residues of mutant calreticulin are required for its oncogenic activity. In work proposed here, I will characterise the role of novel interaction partners of mutant calreticulin in the development of myeloproliferative neoplasms. Moreover, I will determine how mutant calreticulin aberrantly binds to its partners and assess the necessity of this binding in mutant calreticulin cell proliferation. Dr. Mullaly’s group has also shown that mutant calreticulin loses its chaperone activity. In a second approach, I will therefore determine whether mutant calreticulin induces proteome variations such as aberrantly folded proteins at the cell surface. These non-canonical proteins would, by definition, only be present on calreticulin mutated, malignant cells and therefore constitute ideal targets of future immunological therapy. I anticipate identifying non-canonical protein isoforms due to the aberrant chaperone activity of mutant calreticulin. Candidate isoforms will be confirmed and subsequently validated in primary cells.

费城--阴性的骨髓增殖性肿瘤包括一组恶性血液疾病。骨髓增殖性肿瘤的遗传图景被很好地描述，钙网蛋白是仅次于JAK2的第二大常见突变基因。在高达40%的骨髓增生性肿瘤患者中发现了钙网织蛋白突变。此外，钙网蛋白和JAK2V617F突变是互斥的。所有的钙网织蛋白突变都聚集在最后一个编码外显子上，并导致C-末端“KDEL”序列的缺失，该序列通常将野生型钙网织蛋白保留到内质网中，在内质网中它扮演伴侣蛋白的角色。两个最显著的突变(类型I和类型II)都会导致移码，产生一个常见的突变型特异的36个氨基酸的C末端多肽。在新的C末端，带负电荷的氨基酸被带正电荷的氨基酸取代，主要是精氨酸和赖氨酸。最近，突变型钙网蛋白致癌的一种机制已被阐明。穆拉利博士的实验室表明，突变的钙网蛋白与血小板生成素受体产生致病作用，以不依赖于血小板生成素的方式激活下游信号通路。此外，已证明突变的钙网蛋白C末端的正静电电荷和突变的钙网蛋白的凝集素结合残基都是其致癌活性所必需的。在这里提出的工作中，我将描述突变型钙网蛋白的新型相互作用伙伴在骨髓增生性肿瘤发展中的作用。此外，我将确定突变的钙网状蛋白如何异常地与其伴侣结合，并评估这种结合在突变的钙网状蛋白细胞增殖中的必要性。穆拉利博士的研究小组还发现，突变的钙网蛋白失去了其伴侣活性。因此，在第二种方法中，我将确定突变的钙网蛋白是否会导致蛋白质组的变异，例如细胞表面的异常折叠蛋白质。根据定义，这些非规范蛋白只存在于钙网蛋白突变的恶性细胞上，因此成为未来免疫治疗的理想靶点。我预计将鉴定由于突变的钙网网蛋白的异常伴侣活性而导致的非规范蛋白亚型。候选异构体将得到确认，并随后在原代细胞中得到验证。

项目成果

BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells

• DOI: 10.1038/s41419-019-2203-z
• 发表时间: 2020-01-06
• 期刊: CELL DEATH & DISEASE
• 影响因子: 9
• 作者: Afreen, Sehar;Bohler, Sheila;Erlacher, Miriam
• 通讯作者: Erlacher, Miriam

Enhanced expression of the sphingosine-1-phosphate-receptor-3 causes acute myelogenous leukemia in mice

1-磷酸-鞘氨醇受体-3 表达增强导致小鼠急性髓性白血病

• DOI: 10.1038/s41375-019-0577-7
• 发表时间: 2020
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Vorbach S;Gründer A;Zhou F;Koellerer C;Jutzi JS;Simoni M;Riccetti L;Valk PJ;Sanders MA;Müller-Tidow C;Nofer JR;Pahl HL
• 通讯作者: Pahl HL

Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice

• DOI: 10.1371/journal.pone.0228362
• 发表时间: 2020-02-04
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Staehle, Hans F.;Heinemann, Johannes;Jutzi, Jonas Samuel
• 通讯作者: Jutzi, Jonas Samuel