Keck School of Medicine of University of Southern California, Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, Los Angeles, California, 90033, USA.
University of Southern California, Department of Molecular and Computational Biology, Los Angeles, CA, 90089-2910, USA.
Sci Rep. 2017 Aug 1;7(1):7029. doi: 10.1038/s41598-017-07356-9.
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.
基因组转座元件 (TEs) 约占人类基因组的一半。TE 的表达被认为具有潜在的危害性，因为它可能导致插入突变和基因组不稳定。然而，最近的研究表明，TEs 参与了免疫介导的细胞清除。去甲基化剂可以增加癌细胞中 TEs 的表达，诱导“病毒模拟”，导致干扰素信号和癌细胞杀伤。为了研究 TEs 在急性髓系白血病 (AML) 发病机制中的作用，我们研究了 AML 几个细胞群中 TE 的表达情况，同时跟踪其发展（前白血病造血干细胞、白血病干细胞 [LSCs] 和白血病细胞）。LSCs 对化疗有抵抗力，是复发的储库，其 TEs 和干扰素途径受到明显抑制。同样，高危骨髓增生异常综合征 (MDS) 病例的 TEs 抑制程度远远高于低危病例。我们提出 TE 抑制是 AML 和 MDS 中免疫逃避的一种机制。TE 的抑制与几个已知调节 TE 表达的基因的上调同时发生，如 RNA 解旋酶和自噬基因。因此，我们已经确定了潜在的途径，可以通过 AML 和 MDS 中的 TEs 来靶向激活癌症免疫原性。
