Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells 1 , 2 . The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system 3 , 4 and in haematopoietic cancers 5 . JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2 -mutated clones 6 , 7 , prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1 , a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2–ERK signalling and the maintenance of JAK2 V617F malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2 . Inhibition of YBX1, a downstream target of the Janus kinase JAK2, sensitizes myeloproliferative neoplasm cells to JAK and could provide a means to eradicate such cells in human haematopoietic cancers.

中文翻译：

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剪接因子 YBX1 介导 JAK2 突变肿瘤的持续存在

Janus 激酶 (JAK) 介导对造血细胞中细胞因子、激素和生长因子的反应 1, 2。JAK 基因 JAK2 在老化的造血系统 3、4 和造血系统癌症 5 中经常发生突变。JAK2 突变组成性激活下游信号，是骨髓增生性肿瘤 (MPN) 的驱动因素。在临床使用中，JAK 抑制剂对 JAK2 突变克隆的整体疾病负担有不同的影响 6 、 7 ，促使我们研究疾病持续存在的机制。在这里，通过深入的磷酸化蛋白质组分析，我们将参与 mRNA 加工的蛋白质鉴定为突变 JAK2 的靶标。我们发现 YBX1（一种 JAK2 翻译后修饰的靶标）的失活使尽管用 JAK 抑制剂治疗但仍然存在的细胞对细胞凋亡敏感，并导致 RNA 错误剪接，富集保留的内含子和破坏细胞外信号调节激酶 (ERK) 信号的转录控制。结合药理学 JAK 抑制，YBX1 失活诱导 JAK2 依赖性小鼠和原代人类细胞凋亡，导致体内恶性克隆消退，并诱导分子缓解。这识别并验证了细胞内在机制，其中差异蛋白磷酸化导致 JAK2-ERK 信号的剪接依赖性改变和 JAK2 V617F 恶性克隆的维持。因此，YBX1 依赖性 ERK 信号的治疗靶向结合 JAK2 抑制可以根除 JAK2 中携带突变的细胞。抑制 YBX1，Janus 激酶 JAK2 的下游靶标，