文章：

JAK2V617F骨髓增殖性肿瘤中Trp53失活的基因组与功能影响

Genomic and functional impact of Trp53 inactivation in JAK2V617F myeloproliferative neoplasms

原文发布日期：2024-01-04

DOI: 10.1038/s41408-023-00969-6

类型: Article

开放获取: 是

英文摘要：

Classical myeloproliferative neoplasms (MPNs) are characterized by the proliferation of myeloid cells and the risk of transformation into myelofibrosis or acute myeloid leukemia (AML) and TP53 mutations in MPN patients are linked to AML. However, JAK2V617F has been reported to impact the TP53 response to DNA damage, suggesting potential overlapping role of TP53 inactivation in MPN. We established a mouse model showing that JAK2V617F/Vav-Cre/Trp53−/− mice displayed a similar phenotype to JAK2V617F/Vav-Cre mice, but their proliferation was outcompeted in competitive grafts. RNA-Seq revealed that half of the genes affected by JAK2V617F were affected by p53-inactivation, including the interferon pathway. To validate this finding, mice were repopulated with a mixture of wild-type and JAK2V617F (or JAK2V617F/Vav-Cre/Trp53−/−) cells and treated with pegylated interferonα. JAK2V617F-reconstituted mice entered complete hematological remission, while JAK2V617F/Vav-Cre /Trp53−/−-reconstituted mice did not, confirming that p53 loss induced interferon-α resistance. KEGG and Gene Ontology analyses of common deregulated genes showed that these genes were mainly implicated in cytokine response, proliferation, and leukemia evolution, illustrating that in this mouse model, the development of MPN is not affected by TP53 inactivation. Taken together, our results show that many genetic modifications induced by JAK2V617F are influenced by TP53, the MPN phenotype may not be. Trp53 loss alone is insufficient to induce rapid leukemic transformation in steady-state hematopoiesis in JAK2V617F MPN, and Trp53 loss may contribute to interferon resistance in MPN.
 

摘要翻译： 

经典骨髓增殖性肿瘤（MPNs）的特征是髓系细胞增殖，并存在向骨髓纤维化或急性髓系白血病（AML）转化的风险，且MPN患者中的TP53突变与AML相关。然而，据报道JAK2V617F会影响TP53对DNA损伤的反应，提示TP53失活在MPN中可能存在重叠作用。我们建立的小鼠模型显示，JAK2V617F/Vav-Cre/Trp53−/−小鼠表现出与JAK2V617F/Vav-Cre小鼠相似的表型，但在竞争性移植中其增殖能力被抑制。RNA-Seq分析发现，受JAK2V617F影响的基因中有半数也受到p53失活的影响，包括干扰素通路。为验证这一发现，我们使用野生型与JAK2V617F（或JAK2V617F/Vav-Cre/Trp53−/−）细胞的混合细胞重建小鼠模型，并用聚乙二醇干扰素α进行治疗。JAK2V617F重建的小鼠达到完全血液学缓解，而JAK2V617F/Vav-Cre/Trp53−/−重建的小鼠则未缓解，证实p53缺失会导致干扰素α耐药。对共同失调基因的KEGG和基因本体分析表明，这些基因主要参与细胞因子反应、增殖和白血病演变，说明在该小鼠模型中MPN的发展不受TP53失活影响。综上所述，我们的结果表明：虽然JAK2V617F诱导的许多遗传改变受TP53影响，但MPN表型可能不受其影响；在JAK2V617F MPN的稳态造血过程中，仅Trp53缺失不足以诱发快速白血病转化；且Trp53缺失可能导致MPN对干扰素耐药。

原文链接：

Genomic and functional impact of Trp53 inactivation in JAK2V617F myeloproliferative neoplasms