Suppression of Transposable Elements in Leukemic Stem Cells

被引：26
作者：
Colombo, Anthony R. [1 ,2 ]
Zubair, Asif [3 ]
Thiagarajan, Devi [1 ,2 ,4 ]
Nuzhdin, Sergey [3 ]
Triche, Timothy J. [1 ,2 ]
Ramsingh, Giridharan [1 ,2 ]
机构：
[1] Univ Southern Calif, Keck Sch Med, Jane Anne Nohl Div Hematol, Los Angeles, CA 90033 USA
[2] Ctr Study Blood Dis, Los Angeles, CA 90033 USA
[3] Univ Southern Calif, Dept Mol & Computat Biol, Los Angeles, CA 90089 USA
[4] NYU, Sch Med, Div Endocrinol, Langone Med Ctr,Study Diabet, New York, NY 10016 USA
来源：
SCIENTIFIC REPORTS | 2017年 / 7卷
关键词：
ACUTE MYELOID-LEUKEMIA; INTERFERON RESPONSE; DNA METHYLATION; DHX9; HELICASE; RETROTRANSPOSITION; TRANSCRIPTION; EXPRESSION; MUTATIONS; EVOLUTION;
D O I：
10.1038/s41598-017-07356-9
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing 'viral mimicry', causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.
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页数：11
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