Suppression of Transposable Elements in Leukemic Stem Cells

Abstract

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.

Role of RN Autophagy Mediated ERV Suppression in Cellular Senescence

“…Nevertheless, it is the type of autophagy cargo, which determines the outcome in terms of longevity and aging. This study is in lieu with the observations in AML patients, where ERV regulation correlates with Lamp2, RNautophagy marker [6]. Senolytic drugs under development targets these surveillance resistant senescent cells.…”

“…ERV suppression as a potential mechanism in modulating immunogenicity regarding AML development [6].…”

“…Transposable elements (TEs) comprise ~50% of human genome and often considered as detrimental, because of their inherent mobile nature [6]. Endogenous retrovirus (ERV) are specialized transposable elements that constitute 8% of human genome and have the ability to transpose through DNA or RNA intermediates [7,8].…”

Transposable Element Expression Predicts Prognosis in Acute Myeloid Leukemia

“…However, recent studies describe their role in promoting cancer cell death via activating immune pathways 7,8 . In this context, we recently showed that leukemic stem cells in AML, which are the most resilient to treatment, have suppressed TE expression 21 . A recent study also reported that TE is suppressed in chemotherapy resistant cancer cells 35 This is the first study demonstrating the utility of TE expression signature in predicting prognosis in cancer.…”

“…TP53 mutation was associated with 6809 AE-non-TE and 40 AE-TE (BH q.value ≤0.05, minimum absolute log-fold-change 0.2). Of the 6809 TP53 mutation specific AE-non-TE, 3918 were clustered into 7 modules with sufficient connectivity metrics as previously described 21 . The 40 AE-TE were correlated to the principle component (PC) 1 of each 7 modules in the TP53 specific-network.…”