Loss of RUNX1 function results in enhanced granulocyte-colony-stimulating factor-mediated mobilization.
Loss of RUNX1 function results in enhanced granulocyte-colony-stimulating factor-mediated mobilization.
复制标题
RUNX1 功能的丧失会导致粒细胞集落刺激因子介导的动员增强。
DOI：
10.1038/bcj.2016.20
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发表时间：
2016
影响因子：
12.8
通讯作者：
Zhang,D-E
中科院分区：
文献类型：
--
作者：
Lam,K;Muselman,A;Du,R;Yan,M;Matsuura,S;Zhang,D-E
RUNX1是一种转录因子，调节造血的许多重要方面。因此，在包括白血病、骨髓增生异常综合征（MDS）、骨髓增生性肿瘤和其他血液恶性肿瘤在内的多种人类疾病中，已经发现正常RUNX1功能因突变或染色体易位而中断。造血干细胞（hsc）依赖于RUNX1的初始规格、分化决定和整体稳态。1,2在最近发表的Chin等人的研究中，3作者报道RUNX1单倍不全导致粒细胞集落刺激因子（G-CSF）超敏。因此，造血干细胞现在也被证明依赖RUNX1与骨髓生态位进行适当的相互作用。本文通过分析RUNX1基因差异表达和RUNX1基因组占用数据，提供了RUNX1介导细胞间相互作用的补充证据。此外，正常RUNX1功能的丧失导致G-CSF治疗时的动员增强，而G-CSF和CXCR4抑制剂AMD3100联合治疗时的动员甚至更多。这些发现表明，在使用HSC动员试剂治疗前应评估RUNX1突变状态。Runx1条件敲除（KO）小鼠已成为研究Runx1破坏如何影响造血的有用工具，因为Runx1在成人中缺失并不致命，并导致骨髓增生性表型。我们使用Ingenuity Pathway Analysis来分析我们之前发表的数据，这些数据来自野生型（WT）和KO小鼠的hsc（定义为谱系−、sca1+、ckit+或LSK）中差异表达的基因，以及小鼠红细胞髓系淋巴细胞（也称为EML） hsc样细胞系中的RUNX1染色质免疫沉淀与深度测序（补充表1）。5有趣的是，顶级网络包括“细胞间信号传导”和“相互作用”等术语。细胞运动和免疫细胞运输’（补充表2），这表明RUNX1可能在介导造血干细胞与骨髓生态位之间的相互作用中起作用。
RUNX1 is a transcription factor that regulates many essential aspects of hematopoiesis. Hence, disruption of normal RUNX1 function by mutations or chromosomal translocations has been found in a variety of human diseases including leukemia, myelodysplastic syndrome (MDS), myeloproliferative neoplasms and other blood malignancies. Hematopoietic stem cells (HSCs) rely on RUNX1 for their initial specification, decision to differentiate and overall homeostasis. 1, 2 From the recently published study by Chin et al., 3 the authors reported that RUNX1 haploinsufficiency results in granulocyte-colony stimulating factor (G-CSF) hypersensitivity. Hence, HSCs have now also been shown to rely on RUNX1 for proper interaction with the bone marrow niche. 3 Here we provide complimentary evidence that RUNX1 may mediate cell-to-cell interactions through analysis of differential gene expression and RUNX1 genome occupancy data. Furthermore, loss of normal RUNX1 function results in enhanced mobilization upon G-CSF treatment, and even more mobilization upon a combination regimen of G-CSF and AMD3100, a CXCR4 inhibitor. These findings suggest that RUNX1 mutation status should be evaluated before treatment with HSC mobilization reagents.Runx1 conditional knockout (KO) mice have served as a useful tool to study how disruption of RUNX1 affects hematopoiesis, as Runx1 deletion in adults is not lethal and results in a myeloproliferative phenotype. 1, 4 We used Ingenuity Pathway Analysis to analyze our previously published data from differentially expressed genes in HSCs (defined as lineage−, sca1+, ckit+ or LSK) from wild-type (WT) and KO mice, and from RUNX1 chromatin immunoprecipitation coupled with deep sequencing in the mouse erythroid myeloid lymphoid (also known as EML) HSC-like cell line (Supplementary Table 1). 5 Interestingly, the top network included terms such as ‘cell-to-cell signaling’and ‘interaction, cellular movement and immune cell trafficking’(Supplementary Table 2), which suggests that RUNX1 may have a role in mediating the interaction between HSCs and the bone marrow niche.