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遗传缺失或精氨酸甲基转移酶 PRMT5 的小分子抑制在 MLL 重排 AML 的小鼠模型中显示出抗肿瘤活性。

Genetic deletion or small-molecule inhibition of the arginine methyltransferase PRMT5 exhibit anti-tumoral activity in mouse models of MLL-rearranged AML.

机构信息

Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.

出版信息

Leukemia. 2018 Feb;32(2):499-509. doi: 10.1038/leu.2017.206. Epub 2017 Jun 30.

DOI:10.1038/leu.2017.206
PMID:28663579
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5865447/
Abstract

The hematological malignancies classified as mixed lineage leukemias (MLL) harbor fusions of the MLL1 gene to partners that are members of transcriptional elongation complexes. MLL-rearranged leukemias are associated with extremely poor prognosis, and response to conventional therapies and efforts to identify molecular targets are urgently needed. Using mouse models of MLL-rearranged acute myeloid leukemia, here we show that genetic inactivation or small-molecule inhibition of the protein arginine methyltransferase PRMT5 exhibit anti-tumoral activity in MLL-fusion protein-driven transformation. Genome-wide transcriptional analysis revealed that inhibition of PRMT5 methyltransferase activity overrides the differentiation block in leukemia cells without affecting the expression of MLL-fusion direct oncogenic targets. Furthermore, we find that this differentiation block is mediated by transcriptional silencing of the cyclin-dependent kinase inhibitor p21 (CDKN1a) gene in leukemia cells. Our study provides pre-clinical rationale for targeting PRMT5 using small-molecule inhibitors in the treatment of leukemias harboring MLL rearrangements.

摘要

被归类为混合谱系白血病 (MLL) 的血液系统恶性肿瘤具有 MLL1 基因与转录延伸复合物成员的融合。MLL 重排的白血病与极差的预后相关，迫切需要对常规疗法和寻找分子靶标做出回应。在这里，我们使用 MLL 重排急性髓细胞白血病的小鼠模型，表明 MLL 融合蛋白驱动转化中，PRMT5 蛋白精氨酸甲基转移酶的遗传失活或小分子抑制具有抗肿瘤活性。全基因组转录分析显示，抑制 PRMT5 甲基转移酶活性可克服白血病细胞中的分化阻滞，而不影响 MLL 融合直接致癌靶标的表达。此外，我们发现这种分化阻滞是由白血病细胞中细胞周期蛋白依赖性激酶抑制剂 p21（CDKN1a）基因的转录沉默介导的。我们的研究为使用小分子抑制剂靶向 PRMT5 治疗携带 MLL 重排的白血病提供了临床前依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b49/5865447/5f95474f676d/nihms947325f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b49/5865447/f8b29bdfe2ec/nihms947325f3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8b49/5865447/5f95474f676d/nihms947325f7.jpg

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