Suppression of Transposable Elements in Leukemic Stem Cells

Colombo, Anthony; Zubair, Asif; Thiagarajan, Devi; Nuzhdin, Sergey V.; Triche, Timothy J.; Ramsingh, Giridharan

doi:10.1101/169524

Cited by 8 publications

(22 citation statements)

References 49 publications

(35 reference statements)

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“…ALUJo, MER11A, LTR14A and others) that were recently described as being prognostic biomarkers in TCGA AML patient samples and where expression of LTR14A, LTR45B, MER77 and Tigger9b are hazardous covariates that correlate with increased AML risk (Colombo et al, 2018). The distinct repeat subtypes identi ed in our study and in Colombo et al, (2017;Colombo et al, 2018) appear to be the most susceptible repeat elements that are found to have altered expression in AML.…”

Section: Expression Analysis Of Distinct Repeat Elements In Amlsupporting

confidence: 64%

“…Collectively, these insights demonstrate separate functions for the dysregulation of distinct repeat subclasses in either the progression or attenuation of human solid tumors. For hematopoietic malignancies, such as AML, only very few studies on the expression/dysregulation of repeat elements were done (Colombo et al, 2017;Colombo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…5B), resulting in less differentiation. Leukemic stem cells have been associated with chemotherapy resistance and higher rates of relapse and show broader down-regulation of repeat elements as compared to leukemic blast cells (Colombo et al, 2017). Drug-tolerant cancer cells also are characterized by profound repression of LINE-1 elements (Guler et al, 2017).…”

Section: The Rep/gene Ratio Model Can Identify Low-risk and High-riskmentioning

confidence: 99%

“…By contrast, therapeutic activation of endogenous retroviruses (ERV) has been found to trigger an innate immune response in human prostate and breast cancer cell lines (Roulois et al, 2015;Chiappinelli et al, 2015), suggesting that some types of cancer maintain a suppressed level of ERV expression in order to evade immune surveillance. The analysis of repeat element expression/dysregulation has recently been extended to several hematological malignancies, particularly Acute Myeloid Leukemia (Colombo et al, 2017;Colombo et al, 2018).…”

mentioning

confidence: 99%

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Repeat to Gene Expression Ratios in Leukemic Blast Cells Can Stratify Risk Prediction in Acute Myeloid Leukemia

Onishi-Seebacher

Sawitzki

Ryan

et al. 2020

Preprint

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BackgroundRepeat elements constitute a large proportion of the human genome and recent evidence indicates that repeat element expression has functional roles in both physiological and pathological states. Specifically for cancer, transcription of endogenous retrotransposons is often suppressed in order to attenuate an anti-tumor immune response, whereas aberrant expression of heterochromatin-derived satellite RNA has been identified as a tumor driver. These insights demonstrate separate functions for the dysregulation of distinct repeat subclasses in either the attenuation or progression of human solid tumors. For hematopoietic malignancies, such as AML, only very few studies on the expression/dysregulation of repeat elements were done. MethodsTo study the expression of repeat elements in acute myeloid leukemia (AML), we performed total-RNA sequencing of healthy CD34+ cells and of leukemic blast cells from primary AML patient material. We also developed an integrative bioinformatic approach that can quantify the expression of repeat transcripts from all repeat subclasses (SINE/ALU, LINE and ERV elements and satellite repeats) in relation to the expression of gene and other non-repeat transcripts. This novel approach can be used as an instructive signature (‘rep/gene’ ratio) for repeat element expression and has been extended to the analysis of poly(A)-RNA sequencing datasets from Blueprint and TCGA consortia that together comprise 120 AML patient samples. ResultsWe identified that repeat element expression is generally down-regulated during hematopoietic differentiation and that relative changes in repeat to gene expression (i.e. ‘rep/gene’ ratios) can stratify risk prediction of AML patients and correlate with overall survival probabilities. A high repeat to gene expression ratio identifies AML patient subgroups with a favorable prognosis, whereas a low repeat to gene expression is prevalent in AML patient subgroups with a poor prognosis. ConclusionsWe developed an integrative bioinformatic approach that defines a general model for the analysis of repeat element dysregulation in physiological and pathological development. We find that changes in repeat to gene expression (‘rep/gene’ ratios) correlate with hematopoietic differentiation and can sub-stratify AML patients into low-risk and high-risk subgroups. Thus, the definition of a ‘rep/gene’ expression ratio can serve as a valuable biomarker for AML and could also provide insights into differential patient response to epigenetic drug treatment.

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Section: Expression Analysis Of Distinct Repeat Elements In Amlsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: The Rep/gene Ratio Model Can Identify Low-risk and High-riskmentioning

confidence: 99%

mentioning

confidence: 99%

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Repeat to Gene Expression Ratios in Leukemic Blast Cells Can Stratify Risk Prediction in Acute Myeloid Leukemia

Onishi-Seebacher

Sawitzki

Ryan

et al. 2020

Preprint

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“…In this regard, evidence suggests that TEs mediated activation of innate immune response facilitate clearance of cancer cells [19,20]. More directly, we recently showed that leukemic stem cells have repressed expression of TEs along with immune pathways [39], indicative of a survival mechanism to evade an innate immune response. Identification and targeting of similar oncogenic-addictions could prove essential therapeutic strategies, as recently shown [40].…”

Section: Discussionmentioning

confidence: 85%

Senescence induction universally activates transposable element expression

2018

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Senescent cells constitutively secrete inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). Previous work has implicated SASP in immune-mediated clearance of senescent cells; however, its regulation remains unknown. Our recent transcriptome profiling study has shown that human senescent human stem and progenitors (s-HSPCs) robustly express genomic transposable elements (TEs) and pathways of inflammation. Furthermore, hypomethylating agents have been previously shown to induce expression of TEs and activate the dsRNA recognition pathway and downstream interferon-stimulated genes, leading to immune mediated cell death. Therefore, to examine whether activation of TEs occurred universally, independent of their modality of senescence induction, we performed transcriptomic analysis in artificially-induced senescent cell-lines and observed a robust activation of TEs. Hence we propose that the expression of TEs might play a role in immune mediated clearance of senescent cells.

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HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

et al. 2022

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Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14 968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8+ T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8+ T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8+ T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy.

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Suppression of Transposable Elements in Leukemic Stem Cells

Abstract: 28Genomic transposable elements (TEs) comprise nearly half of the human genome.

Cited by 8 publications

References 49 publications

Repeat to Gene Expression Ratios in Leukemic Blast Cells Can Stratify Risk Prediction in Acute Myeloid Leukemia

Repeat to Gene Expression Ratios in Leukemic Blast Cells Can Stratify Risk Prediction in Acute Myeloid Leukemia

Senescence induction universally activates transposable element expression

HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

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