Ikaros mutation confers integrin-dependent pre-B cell survival and progression to acute lymphoblastic leukemia

Deletion of the Ikaros DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL. One of the analyses described in this manuscript is the differential gene expression of large preB cells sorted from the bone marrow of WT and IKDN mice. The RNASeq method and Deseq analysis algorithm were employedIkaros DNA结合结构域（Ikaros DNA-binding domain）的缺失可产生显性负性同工型，此类同工型可干扰Ikaros家族的活性，并与人类前体B细胞急性淋巴细胞白血病（B-ALL）的不良预后密切相关。本研究证实，在早期前B细胞中条件性失活Ikaros DNA结合结构域，会使细胞的分化停滞于特定阶段：此阶段中，整合素依赖的微环境黏附会增强丝裂原活化蛋白激酶信号通路活性、细胞增殖与自我更新能力，并减弱前B细胞受体信号通路活性及细胞分化进程。将多克隆IKZF1（Ikaros家族锌指蛋白1）突变型早期前B细胞移植后，可诱导出长潜伏期的寡克隆前B-ALL，这表明Ikaros功能缺失会推动多步骤B细胞致白血病过程。本研究结果阐明了正常前B细胞如何从高度增殖且依赖基质细胞的状态，转变为可启动分化的非依赖基质细胞状态，为IKZF1突变型B-ALL提供了潜在的治疗策略。 本研究手稿中描述的一项分析内容为：从野生型（WT）与Ikaros显性负性（IKDN）小鼠的骨髓中分选得到的大型前B细胞的差异基因表达分析。本次分析采用了RNA测序（RNASeq）技术与DESeq分析算法。