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.

经典骨髓增生性肿瘤 (MPN) 的特点是髓系细胞增殖，并且有转化为骨髓纤维化或急性髓系白血病 (AML) 的风险，MPN 患者的TP53突变与 AML 相关。然而，据报道，JAK2V617F 会影响TP53对 DNA 损伤的反应，表明 TP53 失活在 MPN 中具有潜在的重叠作用。我们建立了一个小鼠模型，显示 JAK2V617F/Vav-Cre/Trp53 ^−/−小鼠表现出与 JAK2V617F/Vav-Cre 小鼠相似的表型，但它们的增殖在竞争性移植物中被击败。 RNA-Seq 显示，受 JAK2V617F 影响的基因中有一半受到 p53 失活的影响，包括干扰素途径。为了验证这一发现，小鼠被重新植入野生型和 JAK2V617F（或 JAK2V617F/Vav-Cre/Trp53 ^−/− ）细胞的混合物，并用聚乙二醇化干扰素α治疗。 JAK2V617F 重组小鼠进入完全血液学缓解，而 JAK2V617F/Vav-Cre /Trp53 ^−/−重组小鼠则没有，这证实了p53缺失诱导了干扰素-α 抵抗。对常见失调基因的 KEGG 和 Gene Ontology 分析表明，这些基因主要与细胞因子反应、增殖和白血病进化有关，说明在该小鼠模型中，MPN 的发展不受 TP53 失活的影响。综上所述，我们的结果表明，JAK2V617F 诱导的许多遗传修饰均受 TP53 影响，而 MPN 表型可能不受 TP53 影响。仅Trp53缺失不足以诱导 JAK2V617F MPN 稳态造血过程中的快速白血病转化，并且Trp53缺失可能导致 MPN 中的干扰素抵抗。