RUNX1 Inhibition Using Lipid Nanoparticle-Mediated Silencing RNA Delivery as an Effective Treatment for Acute Leukemias
RUNX1 Inhibition Using Lipid Nanoparticle-Mediated Silencing RNA Delivery as an Effective Treatment for Acute Leukemias
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DOI：
10.1016/j.exphem.2022.05.001
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发表时间：
2022-08-01
影响因子：
2.6
通讯作者：
Goyama, Susumu
中科院分区：
文献类型：
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作者：
Iida, Kohei;Tsuchiya, Akiho;Goyama, Susumu
转录因子RUNX 1在造血系统的建立和维持中起着关键作用。尽管RUNX 1被认为是一种有益的肿瘤抑制因子，但最近的一些报道描述了RUNX 1在多种造血肿瘤中的促肿瘤作用。在这项研究中，我们使用重复的规则间隔短回文重复序列（CRISPR）/Cas9系统评估了RUNX 1消耗在多种人类白血病细胞系中的作用，并证实RUNX 1实际上是维持白血病增殖所必需的。为了在白血病细胞中实现有效的RUNX 1抑制，我们然后使用两种肿瘤亲性LNP检查了脂质纳米颗粒（LNP）介导的靶向RUNX 1的小干扰（si）RNA的递送的效果。含有RUNX 1靶向siRNA的LNP被有效地掺入髓细胞和T细胞白血病细胞系以及患者来源的原代人急性髓细胞白血病（AML）细胞中，下调RUNX 1表达，诱导细胞周期停滞和凋亡，并在其中表现出生长抑制作用。相反，LNP不能有效地掺入正常脐带血CD 34（+）细胞，表明它们的细胞毒性最小。因此，我们的研究突出了RUNX 1作为抑制白血病发生的潜在治疗靶点，并提供了基于LNP的siRNA递送作为一种有前途的方法来特异性地在白血病细胞中耗尽RUNX 1。(c)2022 ISEH -血液学和干细胞学会。爱思唯尔公司出版All rights reserved.
Transcription factor RUNX1 plays key roles in the establishment and maintenance of the hematopoietic system. Although RUNX1 has been considered a beneficial tumor suppressor, several recent reports have described the tumor-promoting role of RUNX1 in a variety of hematopoietic neoplasms. In this study, we assessed the effect of RUNX1 depletion in multiple human leukemia cell lines using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system, and confirmed that RUNX1 is in fact required for sustaining their leukemic proliferation. To achieve efficient RUNX1 inhibition in leukemia cells, we then examined the effect of lipid nanoparticle (LNP)-mediated delivery of RUNX1-targeting small interfering (si)RNA using two tumor-tropic LNPs. The LNPs containing RUNX1-targeting siRNA were efficiently incorporated into myeloid and T-cell leukemia cell lines and patient-derived primary human acute myeloid leukemia (AML) cells, downregulated RUNX1 expression, induced cell cycle arrest and apoptosis, and exhibited the growth-inhibitory effect in them. In contrast, the LNPs were not efficiently incorporated into normal cord blood CD34(+) cells, indicating their minimum cytotoxicity. Thus, our study highlights RUNX1 as a potential therapeutic target to inhibit leukemogenesis, and provides the LNP-based siRNA delivery as a promising approach to deplete RUNX1 specifically in leukemia cells. (c) 2022 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.