RNA-seq analysis of Jak1 KO and wt LT-HSCs

Previous studies have illustrated the importance of Jak1-mediated cytokine signaling in immunological and neoplastic diseases such that JAK1 inhibition is currently being investigated in clinical trials. However, the role of Jak1 in hematopoietic stem cell (HSC) function has not been delineated. Here we show that conditional Jak1 loss in hematopoietic cells reduces HSCs and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient stem cells exhibit decreased competitiveness in vivo, and are unable to rescue hematopoiesis in the setting of myelosuppression. Jak1-deficient HSCs show increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and do not respond to type I interferons demonstrating Jak1 as a central node for interferon signaling in HSCs. Moreover, the HSC defect induced by Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Our data highlights an essential role for Jak1 in HSC homeostasis and stress response. Overall design: 6 samples per group; group 1: wt, group 2: KO

既往研究已阐明，Janus激酶1（Jak1）介导的细胞因子信号通路在免疫性疾病与肿瘤性疾病中发挥关键作用，因此JAK1抑制剂目前正处于临床试验阶段。然而，Jak1在造血干细胞（hematopoietic stem cell, HSC）功能调控中的作用尚未得到阐明。本研究发现，造血细胞中条件性敲除Jak1会导致造血干细胞数量减少，并显著改变体内淋巴系/髓系分化进程。Jak1缺陷的造血干细胞在体内的竞争能力下降，且无法在骨髓抑制环境中重建造血功能。Jak1缺陷的造血干细胞表现为静息状态增强，无法响应造血应激而进入细胞周期，且对I型干扰素无应答，这表明Jak1是造血干细胞中干扰素信号通路的核心节点。此外，通过表达组成型激活的Jak2等位基因，无法完全挽救Jak1缺失诱导的造血干细胞缺陷。本研究数据证实，Jak1在造血干细胞稳态维持与应激应答中发挥不可或缺的作用。实验整体设计：每组设置6个样本；对照组1：野生型（wild type, wt），实验组2：基因敲除型（knockout, KO）