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Trompouki, E.

Publications and source records attributed to Trompouki, E..

8 recordsLinked to original sources
bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗
bioRxiv2024

p16High immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16High immune cells play a key role in establishing disease tolerance. We found that the FDA-approved BNT162b2 mRNA COVID-19 vaccine is a potent and rapid inducer of p16High immune subsets both in mice and humans. In turn, p16High immune cells were indispensable for counteracting different lethal conditions, including LPS-induced sepsis, acute SARS-CoV-2 infection and ionizing irradiation. Mechanistically, we propose that activation of TLR7 or a low physiological activity of STING is sufficient to induce p16High immune subset that, in turn, establishes a low adenosine environment and disease tolerance. Furthermore, containing these signals within a beneficial range by deleting MDA5 that appeared sufficient to maintain a low activity of STING, induces p16High immune cells and delays organ deterioration upon aging with improved healthspan. Our data highlight the beneficial role of p16High immune subsets in establishing a low adenosine environment and disease tolerance.

cell biology↗
bioRxiv2024

cGAS-STING is responsible for aging of telomerase deficient zebrafish.

Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type I interferon inflammation and senescence. However, the consequences of these events to the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double mutants and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in ter t mutants resulted in reduced senescence, increased cell proliferation, and low inflammation despite similar short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and low p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, delayed cachexia, and cancer incidence, resulting in increased healthspan and lifespan of telomerase mutants.

cell biology↗
bioRxiv2024

Targeting Heterochromatin Eliminates Malignant Stem Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.

cancer biology↗
bioRxiv2023

PD-L1 blockade immunotherapy rewires cancer emergency myelopoiesis

Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Herein, we reveal that immunotherapy with PD-L1 blockage antibody (PDL1) in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, from both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice shifting towards an inflammatory state. Functionally, transplantation of HSPCs isolated from PDL1-treated tumor-bearing mice exhibited resistance to cancer-associated myelopoiesis as evident by the generation of reduced frequencies of myeloid-derived suppressor cells (MDSCs) compared to cells from control-treated mice. Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of emergency myelopoiesis.

immunology↗
bioRxiv2020

ADA2 is a lysosomal DNase regulating the type-I interferon response

Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic DNase activity. Deletion of ADA2 increased the production of cGAMP and type I interferons upon exposure to dsDNA, which was reverted by ADA2 overexpression or deletion of STING. Our results identify a new level of control in the nucleic acid sensing machinery and provide a mechanistic explanation for the pathophysiology of autoinflammation in DADA2. One Sentence SummaryADA2 is a lysosomal nuclease controlling nucleic acid sensing and type I interferon production.

immunology↗
bioRxiv2020

DOT1L Methyltransferase Activity Preserves SOX2-Enhancer Accessibility And Prevents Activation of Repressed Genes In Murine Stem Cells

BackgroundDuring cellular differentiation, the chromatin landscape changes dynamically and contributes to the activation of cell-type specific transcriptional programs. Disruptor of telomeric silencing 1-like (DOT1L) is a histone methyltransferase that mediates mono-, di- and trimethylation of lysine 79 of histone H3 (H3K79me1, 2, 3). Its enzymatic activity is critical for driving cellular differentiation into cardiomyocytes, chondrocytes and neurons, from embryonic or other type of stem cells in physiological settings. Ectopic localization of DOT1L in MLL-rearranged leukemias is causative for leukemogenesis and relapse. Little is known about the causal relevance of DOT1L methyltransferase activity in the global chromatin context and how its enzymatic function affects transcriptional and global chromatin states. Recent reports conducted in leukemia cell models have suggested that deposition of H3K79me2 may be critical to preserve histone H3K27 acetylation (ac) and enhancer activity, and to sustain expression of highly transcribed genes. If and to what extent DOT1L affects chromatin states and enhancer activity during physiological differentiation processes is currently unknown. ResultsWe measure global changes of seven histone modifications during the differentiation process via high-throughput and quantitative ChIP-seq in an in-vitro neuronal differentiation model of mouse embryonic stem cells (mESC). We observe that H3K27ac globally decreases, whereas H3K79me2 globally increases during differentiation, while other modifications remain globally unaltered. Pharmacological inhibition of DOT1L in mESC and mESC-derived neural progenitors results in decreased expression of highly transcribed genes and increased expression of normally repressed genes. Acute DOT1L inhibition primes neural progenitors towards a mature differentiation state. Transcriptional downregulation associates with decreased accessibility of enhancers specifically bound by the master regulator SOX2. ConclusionsIn-vitro neuronal differentiation couples with a genome-wide accumulation of H3K79me2, never described previously in mammalian cells. Acute inhibition of DOT1L is sufficient to initiate a defined transcriptional program, which biases the transcriptome of neural progenitor cells towards neuronal differentiation. H3K79me2 is not generally causative for maintaining transcriptional levels at a genome-wide scale. In contrast, DOT1L inactivation reduces the chromatin accessibility of enhancers bound by SOX2 in-vivo, thereby reducing the expression level of a restricted number of genes. Our work establishes that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.

genomics↗