Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.
Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.
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DOI：
10.1158/2159-8290.cd-15-1434
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发表时间：
2016-04
期刊：
影响因子：
28.2
通讯作者：
Mullally A
中科院分区：
文献类型：
--
作者：
Elf S;Abdelfattah NS;Chen E;Perales-Patón J;Rosen EA;Ko A;Peisker F;Florescu N;Giannini S;Wolach O;Morgan EA;Tothova Z;Losman JA;Schneider RK;Al-Shahrour F;Mullally A
大约 40% 的骨髓增生性肿瘤 (MPN) 患者中存在钙网蛋白 (CALR) 体细胞突变，但突变 CALR 的致癌机制仍不清楚。在这里，我们证明突变 CALR 的单独表达足以在小鼠中产生 MPN，并概括了 CALR 突变 MPN 患者的疾病表型。我们进一步表明，血小板生成素受体 MPL 是通过 JAK-STAT 途径激活突变 CALR 驱动的转化所必需的，从而使突变 CALR 转化的造血细胞对 JAK2 抑制敏感。最后，我们证明突变体 CALR 的致癌性取决于突变体蛋白 C 端的正静电荷，这对于突变体 CALR 和 MPL 之间的物理相互作用是必需的。总之，我们的研究结果阐明了癌症发病机制的新范式，并揭示了 CALR 突变如何诱导 MPN。
Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN) but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of CALR-mutant MPN patients. We further show that the thrombopoietin receptor, MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN.