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Acute myeloid leukemia cells functionally compromise hematopoietic stem/progenitor cells inhibiting normal hematopoiesis through the release of extracellular vesicles

ABSTRACT: Acute myeloid leukemia cells functionally compromise hematopoietic stem/progenitor cells inhibiting normal hematopoiesis through the release of extracellular vesicles

PROVIDER: PRJNA783281 | ENA |

REPOSITORIES: ENA

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Acute myeloid leukemia cells functionally compromise hematopoietic stem/progenitor cells inhibiting normal hematopoiesis through the release of extracellular vesicles

Project description:Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal disorder of hematopoietic stem/progenitor cells (HSPCs). It is not well known how leukemia cells alter hematopoiesis promoting tumor growth and leukemic niche formation. In this study, we investigated how AML deregulates the hematopoietic process of HSPCs through the release of extracellular vesicles (EVs). First, we found that AML cells released a heterogeneous population of EVs (AML-EVs) containing microRNAs involved in AML pathogenesis. Notably AML-EVs were able to influence the fate of HSPCs modifying their transcriptome. In fact, a gene expression profile of AML-EV-treated HSPCs identified approximately 923 down and 630 up-regulated genes involved in hematopoiesis/differentiation, inflammatory cytokine production and cell movement. Indeed, most of the downregulated genes are targeted by AML-EV-derived miRNAs. Furthermore, we demonstrated that AML-EVs were able to affect HSPCs phenotype, modifying several biological functions, such as inhibiting cell differentiation and clonogenicity, activating inflammatory cytokine production and compromising cell movement. Indeed, a redistribution of HSPC populations was observed in AML-EV treated cells with a significant increase in the frequency of common myeloid progenitors and a reduction in granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors. This effect was accompanied by a reduction in HSPC colony formation. AML-EV treatment of HSPCs increased the levels of CCL3, IL1B and CSF2 cytokines, involved in the inflammatory process and in cell movement, and decreased CXCR4 expression associated with a reduction of SDF-1 mediated-migration. In conclusion, this study demonstrates the existence of a powerful communication between AML cells and HSPCs, mediated by EVs, which suppresses normal hematopoiesis and potentially contributes to create a leukemic niche favorable to neoplastic development.

2022-03-11 | GSE189492 | GEO

Acute Myeloid Leukemia Cells Functionally Compromise Hematopoietic Stem/Progenitor Cells Inhibiting Normal Hematopoiesis Through the Release of Extracellular Vesicles.

Project description:Acute myeloid leukemia (AML) is an aggressive and heterogeneous clonal disorder of hematopoietic stem/progenitor cells (HSPCs). It is not well known how leukemia cells alter hematopoiesis promoting tumor growth and leukemic niche formation. In this study, we investigated how AML deregulates the hematopoietic process of HSPCs through the release of extracellular vesicles (EVs). First, we found that AML cells released a heterogeneous population of EVs containing microRNAs involved in AML pathogenesis. Notably, AML-EVs were able to influence the fate of HSPCs modifying their transcriptome. In fact, gene expression profile of AML-EV-treated HSPCs identified 923 down- and 630 up-regulated genes involved in hematopoiesis/differentiation, inflammatory cytokine production and cell movement. Indeed, most of the down-regulated genes are targeted by AML-EV-derived miRNAs. Furthermore, we demonstrated that AML-EVs were able to affect HSPC phenotype, modifying several biological functions, such as inhibiting cell differentiation and clonogenicity, activating inflammatory cytokine production and compromising cell movement. Indeed, a redistribution of HSPC populations was observed in AML-EV treated cells with a significant increase in the frequency of common myeloid progenitors and a reduction in granulocyte-macrophage progenitors and megakaryocyte-erythroid progenitors. This effect was accompanied by a reduction in HSPC colony formation. AML-EV treatment of HSPCs increased the levels of CCL3, IL-1B and CSF2 cytokines, involved in the inflammatory process and in cell movement, and decreased CXCR4 expression associated with a reduction of SDF-1 mediated-migration. In conclusion, this study demonstrates the existence of a powerful communication between AML cells and HSPCs, mediated by EVs, which suppresses normal hematopoiesis and potentially contributes to create a leukemic niche favorable to neoplastic development.

| S-EPMC8965808 | biostudies-literature

A PP2A-Integrator complex regulates transcriptional pause-release by functionally opposing CDK9

Project description:A PP2A-Integrator complex regulates transcriptional pause-release by functionally opposing CDK9

| PRJNA607046 | ENA

TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scMULT]

Project description:Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. In this study we perform Multiome single cell sequencing of PBMCs from COVID19 patients and patients with clonal hematopoiesis.

2024-08-14 | GSE210432 | GEO

TET2 Mutant Clonal Hematopoiesis Enhances Severity of COVID-19 Related Cytokine Release Syndrome and is Associated with Increased Mortality [scRNA-seq]

Project description:Coronavirus disease 2019 (COVID-19) is associated with significant morbidity and mortality, albeit with considerable heterogeneity among affected individuals. Emerging evidence points towards an important role of preexisting host factors, such as a deregulated inflammatory response at the time of infection. Here, we demonstrate the negative impact of clonal hematopoiesis, a prevalent clonal disorder of ageing individuals, on COVID-19-related cytokine release severity and mortality. In this study we perform single cell RNA sequencing of PBMCs from COVID19 patients and patients with clonal hematopoiesis.

2024-08-14 | GSE210433 | GEO

A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

Project description:A single cell framework identifies functionally and molecularly distinct multipotent progenitors in adult human hematopoiesis

| PRJNA1091798 | ENA

Leukemic hematopoiesis

Project description:Leukemic hematopoiesis

| PRJNA881262 | ENA

Gain-of-function Variants in SMAD4 compromise Respiratory Epithelial cells

Project description:Gain-of-function Variants in SMAD4 compromise Respiratory Epithelial cells

| PRJNA1127656 | ENA

Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival

Project description:Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in Atg5/7-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.

2025-05-07 | PXD057003 | Pride

E-cigarettes compromise the gut barrier, trigger inflammation

Project description:E-cigarettes compromise the gut barrier, trigger inflammation

| PRJNA678641 | ENA