Clonal hematopoiesis (CH) is a common premalignant state in the blood and confers an increased risk of blood cancers and all-cause mortality. Identification of therapeutic targets in CH has been hindered by the lack of an ex vivo platform amenable for studying primary hematopoietic stem and progenitor cells (HSPCs). Here, we utilize an ex vivo co-culture system of HSPCs with bone marrow endothelial cells to perform CRISPR/Cas9 screens in mutant HSPCs. Our data reveal that loss of the histone demethylase family members Kdm3b and Jmjd1c specifically reduces the fitness of Idh2- and Tet2-mutant HSPCs. Kdm3b loss in mutant cells leads to decreased expression of critical cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to inhibition of downstream JAK2 signaling. Our study nominates an epigenetic regulator and an epigenetically regulated receptor signaling pathway as genotype-specific therapeutic targets and provides a scalable platform to identify genetic dependencies in mutant HSPCs.

中文翻译：

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原代造血干细胞中的 CRISPR 依赖性筛选将 KDM3B 识别为 IDH2 和 TET2 突变细胞中的基因型特异性漏洞


克隆造血（CH）是血液中常见的癌前状态，会增加患血癌和全因死亡率的风险。由于缺乏适合研究原代造血干细胞和祖细胞 (HSPC) 的离体平台，CH 治疗靶标的鉴定受到阻碍。在这里，我们利用 HSPC 与骨髓内皮细胞的离体共培养系统在突变 HSPC 中进行 CRISPR/Cas9 筛选。我们的数据表明，组蛋白去甲基化酶家族成员 Kdm3b 和 Jmjd1c 的丢失会显着降低 Idh2 和 Tet2 突变 HSPC 的适应性。突变细胞中 Kdm3b 的缺失会导致包括 Mpl 在内的关键细胞因子受体的表达降低，从而使突变 HSPC 更容易受到下游 JAK2 信号传导的抑制。我们的研究指定表观遗传调节剂和表观遗传调节受体信号通路作为基因型特异性治疗靶点，并提供了一个可扩展的平台来识别突变 HSPC 的遗传依赖性。