Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms
Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms
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DOI：
10.1038/s41586-020-2968-3
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发表时间：
2020-11-25
期刊：
影响因子：
64.8
通讯作者：
Heidel, Florian H.
中科院分区：
文献类型：
--
作者：
Jayavelu, Ashok Kumar;Schnoder, Tina M.;Heidel, Florian H.
抑制Janus激酶JAK 2的下游靶点YBX 1可使骨髓增生性肿瘤细胞对JAK敏感，并可提供一种根除人类造血系统癌症中此类细胞的方法。Janus激酶（JAK）介导对造血细胞中细胞因子、激素和生长因子的应答（1，2）。JAK基因JAK 2在衰老的造血系统（3，4）和造血系统癌症（5）中经常突变。JAK 2突变组成性激活下游信号传导，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JAK 2突变克隆的总体疾病负担具有混合效应（6，7），促使我们研究疾病持续性的机制。在这里，通过深入的磷酸化蛋白质组分析，我们确定参与mRNA加工的蛋白质作为突变JAK 2的靶点。我们发现，YBX 1（JAK 2的后修饰靶点）的失活使细胞敏感，尽管用JAK抑制剂处理，但细胞仍然存在凋亡，并导致RNA错误剪接，保留内含子的富集和细胞外信号调节激酶（ERK）信号传导的转录控制的破坏。结合药理学JAK抑制，YBX 1失活诱导JAK 2依赖性小鼠和原代人细胞凋亡，导致体内恶性克隆消退，并诱导分子缓解。这鉴定并验证了细胞内在机制，其中差异蛋白磷酸化导致JAK 2-ERK信号传导的剪接依赖性改变和JAK 2（V617 F）恶性克隆的维持。因此，YBX 1依赖性ERK信号传导的治疗靶向与JAK 2抑制相结合可以根除JAK 2中携带突变的细胞。
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.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.