A non-canonical enzymatic function of PIWIL4 maintains genomic integrity and leukemic growth in AML

生物 髓系白血病 造血 干细胞 祖细胞 基因 核糖核酸 髓样 细胞生物学 癌症研究 遗传学
作者
Shiva Bamezai,Alex Jose Pulikkottil,Tribhuwan Yadav,Vegi M. Naidu,Julia Mueller,Jasmin Mark,Tamoghna Mandal,Kristin Feder,Susann Lehle,Chenlin Song,R. Rosler,Sebastian Wiese,Jessica I. Hoell,Andreas Kloetgen,Aly Karsan,Ankita Kumari,Luke Wojenski,Amit Sinha,Irene González-Menéndez,Leticia Quintanilla-Martı́nez,Elisa Donato,Andreas Trumpp,Elisabeth Kruse,Stephan Hamperl,Lee Zou,Vijay P.S. Rawat,Christian Buske
出处
期刊:Blood [Elsevier BV]
被引量:11
标识
DOI:10.1182/blood.2022018651
摘要

RNA-binding proteins (RBPs) form a large and diverse class of factors many members of which are overexpressed in hematological malignancies. RBPs participate in various processes of mRNA metabolism and prevent harmful DNA:RNA hybrids or R-loops. Here we report that PIWIL4, a germ stem cell-associated RBP belonging to the RNase H-like superfamily, is overexpressed in acute myeloid leukemia patients and is essential for leukemic stem cell function and AML growth, but dispensable for healthy human hematopoietic stem cells. In AML cells, PIWIL4 binds to a small number of known piwi-interacting RNA. It instead largely interacts with mRNA annotated to protein-coding genic regions and enhancers that are enriched for genes associated with cancer and human myeloid progenitor gene signatures. PIWIL4 depletion in AML cells downregulates human myeloid progenitor signature and LSC-associated genes and upregulates DNA damage signalling. We demonstrate that PIWIL4 is an R-loop resolving enzyme that prevents R-loop accumulation on a subset of AML and LSC-associated genes, and maintains their expression. It also prevents DNA damage, replication stress, and activation of the ATR pathway in AML cells. PIWIL4 depletion potentiates sensitivity to pharmacological inhibition of the ATR pathway and creates a pharmacologically actionable dependency in AML cells.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
华仔应助sxhdxwf采纳,获得30
1秒前
奋斗的怀曼完成签到,获得积分10
1秒前
2秒前
2秒前
5秒前
6秒前
6秒前
loong发布了新的文献求助10
7秒前
莫挽完成签到,获得积分10
7秒前
7秒前
8秒前
8秒前
小垃圾完成签到,获得积分10
9秒前
YHT完成签到,获得积分10
9秒前
万能图书馆应助loong采纳,获得10
11秒前
今后应助leonzhou采纳,获得10
11秒前
3080发布了新的文献求助20
12秒前
拖把粘十发布了新的文献求助10
13秒前
14秒前
15秒前
15秒前
Jasper应助芝士奶盖有点咸采纳,获得10
16秒前
16秒前
liiiii发布了新的文献求助10
17秒前
liiiii发布了新的文献求助10
19秒前
liiiii发布了新的文献求助10
19秒前
JamesPei应助认真跳跳糖采纳,获得10
19秒前
20秒前
liiiii发布了新的文献求助10
20秒前
张雯思发布了新的文献求助10
20秒前
WK完成签到,获得积分10
21秒前
21秒前
Muhammad发布了新的文献求助10
22秒前
FashionBoy应助Karol采纳,获得10
24秒前
Michelangelo_微风完成签到,获得积分10
24秒前
平淡汽车完成签到,获得积分10
24秒前
25秒前
徐徐发布了新的文献求助10
28秒前
共享精神应助优秀的莹采纳,获得10
29秒前
29秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989711
求助须知:如何正确求助?哪些是违规求助? 3531864
关于积分的说明 11255235
捐赠科研通 3270505
什么是DOI,文献DOI怎么找? 1804983
邀请新用户注册赠送积分活动 882157
科研通“疑难数据库(出版商)”最低求助积分说明 809176