Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CD4+ T cell-derived IL21 regulates stem cell fate in acute myeloid leukemia by activation of p38-MAPK signaling - IL21R KO experiment

ABSTRACT: Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in acute myeloid leukemia (AML) patients. We identified CD4+ T cell-derived interleukin (IL) 21 as an important negative regulator of self-renewal of murine and human LSCs, but not hematopoietic stem cells. IL21/IL21R signaling favored asymmetric cell division and differentiation in LSCs through accumulation of reactive oxygen species (ROS) and activation of p38-MAPK signaling, resulting in reduced LSCs number and significantly prolonged survival in murine AML models. In human AML, serum IL21 at diagnosis was identified as an independent positive prognostic biomarker for outcome and correlated with better survival and higher complete remission rate in patients that underwent high-dose chemotherapy. IL21 inhibited primary AML LSCs function in vitro by activating ROS and p38-MAPK signaling and this effect was enhanced by cytarabine treatment. Consequently, promoting IL21/IL21R signaling on LSCs may be a novel approach to decrease stemness and increase differentiation in AML.

ORGANISM(S): Mus musculus

PROVIDER: GSE241172 | GEO | 2024/10/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CD4+ T cell-derived IL21 regulates stem cell fate in acute myeloid leukemia by activation of p38-MAPK signaling - IL21KO experiment

Project description:Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in acute myeloid leukemia (AML) patients. We identified CD4+ T cell-derived interleukin (IL) 21 as an important negative regulator of self-renewal of murine and human LSCs, but not hematopoietic stem cells. IL21/IL21R signaling favored asymmetric cell division and differentiation in LSCs through accumulation of reactive oxygen species (ROS) and activation of p38-MAPK signaling, resulting in reduced LSCs number and significantly prolonged survival in murine AML models. In human AML, serum IL21 at diagnosis was identified as an independent positive prognostic biomarker for outcome and correlated with better survival and higher complete remission rate in patients that underwent high-dose chemotherapy. IL21 inhibited primary AML LSCs function in vitro by activating ROS and p38-MAPK signaling and this effect was enhanced by cytarabine treatment. Consequently, promoting IL21/IL21R signaling on LSCs may be a novel approach to decrease stemness and increase differentiation in AML.

2024-10-12 | GSE241171 | GEO

CD4+ T cell-derived IL21 regulates stem cell fate in acute myeloid leukemia by activation of p38-MAPK signaling - Human AMK

2024-10-12 | GSE241170 | GEO

Cisplatin toxicity is counteracted by the activation of the p38/ATF-7 signaling pathway in post-mitotic C. elegans

Project description:Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. We show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.

2023-04-26 | PXD033377 | Pride

Single-cell gene expression analyses reveal distinct self-renewing and proliferating subsets in the leukemia stem cell compartment in murine acute myeloid leukemia

Project description:Standard chemotherapy for acute myeloid leukemia (AML) targets proliferative cells and efficiently induces complete remission; however, many patients relapse and die of their disease. Relapse is caused by leukemia stem cells (LSCs), the cells with self-renewal capacity. Self-renewal and proliferation are mutually exclusive in normal hematopoietic stem cells (HSCs) in steady state conditions. If these functions are also mutually exclusive in LSCs, then antiproliferative therapies may fail to target self-renewal, allowing for relapse. We investigated whether proliferation and self-renewal are mutually exclusive in LSCs as they often are in HSCs. Using single-cell RNA sequencing, we identified distinct transcriptional profiles within LSCs of Mll-AF9/NRASG12V murine AML. We used single-cell qPCR and found that these genes were also differentially expressed in primary human LSCs and normal human HSPCs. A smaller subset of these genes was upregulated in LSCs relative to HSPCs; this smaller subset of genes constitutes “LSC-specific” genes in human AML. To assess the differences between these profiles, we identified cell surface markers, CD69 and CD36, whose genes were differentially expressed between these profiles. Using in vivo mouse reconstitution assays, we found that only CD69High LSCs were capable of self-renewal and were poorly proliferative. In contrast, CD36High LSCs were unable to transplant leukemia but were highly proliferative. These data demonstrate that the transcriptional foundations of self-renewal and proliferation are distinct in LSCs as they often are in normal stem cells and suggest that therapeutic strategies that target self-renewal, in addition to proliferation, are critical to prevent relapse and improve survival in AML.

2019-11-25 | GSE140896 | GEO

CD34+ AML cells with low mitochondrial activity show increased expression of stemness-genes and can be targeted by the BCL-2 inhibitor Venetoclax

Project description:It has been shown that AML cells with low levels of reactive oxygen species (ROS) have characteristics of LSCs as defined by in vitro and in vivo experiments. We investigated how distinct ROS levels within the stem cell enriched AML CD34+ cell fraction correlate with cellular functions and characteristics such as morphology, metabolic activity, gene expression and drug responsiveness. The results demonstrate that CD34+ AML cells with low ROS levels corresponded with the CD34+/CD38- AML subfraction and showed significantly increased expression of stemness-associated genes and negative regulators of signaling and had a lower mitochondrial number and activity. Moreover, CD34+ AML cells with low ROS levels could be efficiently targeted with the BCL-2 inhibitor Venetoclax despite their similar BCL-2 expression levels compared to the less sensitive CD34+ AML fraction with high ROS levels.

2020-05-24 | GSE131422 | GEO

RNA-seq of Tfh IL21+ single producers and Tfh IL21+ IL10+ double producers

Project description:RNA-seq of Tfh IL21+ single producers and Tfh IL21+ IL10+ double producers

| PRJNA435612 | ENA

Ripk3 signaling regulates the number and function of HSCs during stress and represses radiation-induced leukemia in mice

Project description:We found that Ripk3 signaling selectively regulates both the number and function of hematopoietic stem cells (HSCs) during stress conditions and inhibits ionizing radiation (IR)-induced leukemia development in mice. During serial transplantation, which stimulates a chronic Ripk3 activation in HSCs, Ripk3 promotes the loss of HSCs via Mlkl-mediated necroptosis and impairs HSC function by inducing ROS-p38-p16 mediated senescence. In response to 6Gy of IR, which induces the activation of p53-p21-mediated cell cycle arrest/senescence in HSCs, Ripk3 is required for the activation of NF-κB and permits the survival of the senescent cells. However, in response to multiple low doses of IR (1.75 × 4), Ripk3 signaling inhibits leukemia development by inducing ROS-p38-p16-mediated senescence and repressing Ire1α-Xbp1-Dnajb8 UPR fitness in pre-leukemic stem cells (pre-LSCs) and also inducing Mlkl-dependent clearance of pre-LSCs. Mlkl deletion prevents IR-induced loss of HSCs and slightly accelerates leukemia development in mice, while Ripk3 deletion represses both necroptotic and senescence signals in pre-LSCs and significantly accelerates IR-induced leukemia development. Our study suggests that immediately after high dose IR, temporal inhibition of Ripk3-NF-κB signaling might help to prevent long-term residual damage (LT-RDs) in bone marrow by eliminating the IR-induced senescent HSCs. However, in response to low dose radiation, induced activation of Ripk3 signaling at the pre-leukemia stage might help to prevent the accumulation of mutant HSCs and the development of leukemia.

2022-06-29 | GSE139143 | GEO

The important role of GPR84 in MLL leukemogenesis

Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.

2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress

Early response evaluation by single cell signaling profiling in acute myeloid leukemia

Project description:Aberrant pro-survival signaling is a hallmark of cancer cells, but the response to chemotherapy is poorly understood. In this study, we investigate the initial signaling response to standard induction chemotherapy in a cohort of 32 acute myeloid leukemia (AML) patients, using 36-dimensional mass cytometry. Through supervised and unsupervised machine learning approaches, we find that reduction of extracellular-signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation in the myeloid cell compartment 24h post-chemotherapy is a significant predictor of patient 5-year overall survival in this cohort. Validation by RNA sequencing show induction of MAPK target gene expression in patients with high phospho-ERK1/2 24h post-chemotherapy, while proteomics confirms an increase of the p38 prime target MAPK activated protein kinase 2 (MAPKAPK2). In this study, we demonstrate that mass cytometry can be a valuable tool for early response evaluation in AML and elucidate the potential of functional signaling analyses in precision oncology diagnostics.

2022-12-02 | GSE218664 | GEO

Lysosomal damage triggers a p38 MAPK-dependent phosphorylation cascade to promote lysophagy via the small heat shock protein HSP27

Project description:Maintenance of lysosomal integrity is essential for cell viability. Upon injury, lysosomes may be targeted for degradation via a form of selective autophagy known as lysophagy, in which autophagosomes engulf damaged lysosomes following the recruitment of adaptor proteins. One of these adaptors, SQSTM1/p62, promotes lysophagy via liquid-like phase separation on damaged lysosomes. The formation of p62 condensates is regulated by the heat shock protein HSP27. Here, we demonstrate a direct interaction between HSP27 and p62. We used structural modeling to predict the binding interface between HSP27 and p62, and found several disease-associated mutations that map to this interface and disrupt the interaction. We then used proteomics to identify post-translational modifications of HSP27 that determine HSP27 recruitment to stressed lysosomes, finding robust phosphorylation at Serine residues 15, 78, and 82. We characterized the signaling mechanism leading to HSP27 phosphorylation. We find that p38 MAPK and its effector kinase MK2 are activated upon lysosomal damage by the kinase mTOR and the production of intracellular reactive oxygen species (ROS). Increased ROS activates p38 MAPK, which in turn allows MK2-dependent phosphorylation of HSP27. Either depletion of HSP27 or inhibition of HSP27 phosphorylation alters the liquidity of p62 condensates, significantly inhibiting p62-dependent lysophagy. Thus, we define a novel lysosomal quality control mechanism in which lysosomal injury triggers a p38 MAPK/MK2 signaling cascade regulating p62-dependent lysophagy. Further, this signaling cascade is activated by a variety of cellular stressors, including oxidative and heat stress, suggesting that other forms of selective autophagy may be regulated by p38 MAPK/MK2/HSP27.

2024-10-22 | PXD051927 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data