@article{e066429ed0644117997fa7b1fc475c7c,
title = "Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia",
abstract = "Transposable elements or transposons are major players in genetic variability and genome evolution. Aberrant activation of long interspersed element-1 (LINE-1 or L1) retrotransposons is common in human cancers, yet their tumor-type-specific functions are poorly characterized. We identified MPHOSPH8/MPP8, a component of the human silencing hub (HUSH) complex, as an acute myeloid leukemia (AML)-selective dependency by epigenetic regulator-focused CRISPR screening. Although MPP8 is dispensable for steady-state hematopoiesis, MPP8 loss inhibits AML development by reactivating L1s to induce the DNA damage response and cell cycle exit. Activation of endogenous or ectopic L1s mimics the phenotype of MPP8 loss, whereas blocking retrotransposition abrogates MPP8-deficiency-induced phenotypes. Expression of AML oncogenic mutations promotes L1 suppression, and enhanced L1 silencing is associated with poor prognosis in human AML. Hence, while retrotransposons are commonly recognized for their cancer-promoting functions, we describe a tumor-suppressive role for L1 retrotransposons in myeloid leukemia.",
author = "Zhimin Gu and Yuxuan Liu and Yuannyu Zhang and Hui Cao and Junhua Lyu and Xun Wang and Annika Wylie and Newkirk, {Simon J.} and Jones, {Amanda E.} and Michael Lee and Botten, {Giovanni A.} and Mi Deng and Kathryn Dickerson and Zhang, {Cheng Cheng} and Wenfeng An and Abrams, {John M.} and Jian Xu",
note = "Funding Information: We thank S. J. Morrison, R. J. DeBerardinis, H. Zhu, M. Agathokleous and S. Chung at UTSW for discussion, G. G. Wang at the University of North Carolina at Chapel Hill for the OCI-AML3 cell line, J. Wysocka at Stanford University for assistance with the RNA-seq and ChIP–seq pipelines and other Xu laboratory members for technical support. Y.L. was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) training grant no. RP160157. A.W. was supported by National Institutes of Health (NIH) Cancer Biology Training grant no. T32CA124334. W.A. was supported by NIH grant nos. R21OD017965 and R15GM131263 and the Markl Faculty Scholar Fund. J.X. is a Scholar of the Leukemia & Lymphoma Society and a Scholar of the American Society of Hematology. This work was supported by NIH grant nos. R01CA230631 and R01DK111430 (to J.X.), R01CA248736 (to C.C.Z.), R01GM115682 and R01CA222579 (to J.M.A.), by CPRIT grant nos. RR140025, RP180504, RP180826 and RP190417 (to J.X.) and RP170086 (to J.M.A.), by the Leukemia Texas Foundation research award and by the Welch Foundation grant no. I-1942 (to J.X.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
doi = "10.1038/s41588-021-00829-8",
language = "English (US)",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
}