Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.

JAK2的突变基因是衰老造血系统和骨髓肿瘤中的常见异常。虽然 JAK 抑制剂有效地减少了由组成型活性突变的 JAK2 激酶诱导的过度炎症，但恶性克隆和突变细胞的丰度仍然相当不受影响。在这里，我们试图评估 JAK2 突变克隆的遗传脆弱性。我们将赖氨酸特异性去甲基化酶 KDM4C 鉴定为在 JAK 抑制剂治疗后持续存在的选择性遗传依赖性。人和鼠 JAK2 突变细胞中 KDM4C 的遗传失活导致细胞竞争丧失和增殖减少。这些发现导致人类 JAK2 突变细胞异种移植模型的疾病外显率降低和存活率提高。KDM4C缺失的细胞显示出靶组蛋白残基甲基化和靶基因表达的改变，导致细胞衰老。总之，这些数据将 KDM4C 确立为 JAK2 突变细胞中的特定依赖性和治疗靶点，这对于致癌信号传导和防止衰老的诱导至关重要。