β-Arrestin2 mediates the initiation and progression of myeloid leukemia.
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ABSTRACT:
SUBMITTER: Fereshteh M
PROVIDER: S-EPMC3411976 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Primary myelofibrosis is a myeloproliferative neoplasm associated with significant morbidity and mortality, for which effective therapies are lacking. ?-Arrestins are multifunctional adaptor proteins involved in developmental signaling pathways. One isoform, ?-arrestin2 (?arr2), has been implicated in initiation and progression of chronic myeloid leukemia, another myeloproliferative neoplasm closely related to primary myelofibrosis. Accordingly, we investigated the relationship between ?arr2 and primary myelofibrosis. In a murine model of MPLW515L-mutant primary myelofibrosis, mice transplanted with donor ?arr2-knockout (?arr2-/-) hematopoietic stem cells infected with MPL-mutant retrovirus did not develop myelofibrosis, whereas controls uniformly succumbed to disease. Although transplanted ?arr2-/- cells homed properly to marrow, they did not repopulate long-term due to increased apoptosis and decreased self-renewal of ?arr2-/- cells. In order to assess the effect of acute loss of ?arr2 in established primary myelofibrosis in vivo, we utilized a tamoxifen-induced Cre-conditional ?arr2-knockout mouse. Mice that received Cre (+) donor cells and developed myelofibrosis had significantly improved survival compared with controls. These data indicate that lack of antiapoptotic ?arr2 mediates marrow failure of murine hematopoietic stem cells overexpressing MPLW515L. They also indicate that ?arr2 is necessary for progression of primary myelofibrosis, suggesting that it may serve as a novel therapeutic target in this disease.
| S-EPMC5752278 | biostudies-literature
Project description:ObjectiveTo investigate the role of lncRNA AL645608.3 in the malignant progression of acute myeloid leukemia (AML) cells and explore relevant molecular mechanisms.MethodsThe expression level of AL645608.3 was measured in AML cell lines (THP-1, HL-60, KG-1, and AML-193) via real-time quantitative polymerase chain reaction (RT-qPCR). Small hairpin RNA (shRNA) and open reading frame of AL645608.3 were cloned into lentiviral vectors and were infected into THP-1 and AML-193 cells. The expression of casitas B-lineage lymphoma (CBL), interferon regulatory factor 6 (IRF6), and interferon beta 1 (IFNB1) was detected through RT-qPCR, and western blot. Co-immunoprecipitation (Co-IP) on IRF6 was conducted. Matrix metalloprotease-9 (MMP-9) activity was evaluated via gelatin zymography assay.ResultsLncRNA AL645608.3 was expressed in the four AML cell lines (THP-1, HL-60, KG-1, and AML-193). Silencing AL645608.3 mitigated the expression of IRF6 and IFNB1 but elevated the expression of CBL in THP-1 cells. Oppositely, AL645608.3 overexpression up-regulated the expression of IRF6 and IFNB1 but decreased the expression of CBL in AML-193 cells. Co-IP results proved that AL645608.3 could directly mediate IRF6 activity in THP-1 and AML-193 cells. MMP-9 activity was decreased by AL645608.3 knockdown and was improved by AL645608.3 overexpression in AML-193 cells.ConclusionAL645608.3 is expressed in different AML cell lines, and mediates the expression of CBL, IRF6, IFNB1, and MMP-9. These findings might deepen our comprehension of the molecular mechanisms underlying AML.
| S-EPMC10839383 | biostudies-literature
Project description:beta-Arrestins mediate internalization of plasma membrane receptors. Nephrin, a structural component of the glomerular slit diaphragm, is a single transmembrane spanning receptor and belongs to the family of adhesion molecules. Its mutation causes a hereditary nephrotic syndrome. We report the previously undescribed interaction of beta-arrestin2 with the nephrin C terminus. The phosphorylation status of nephrin Y1193 regulates inversely the binding of beta-arrestin2 and podocin. The Src-family member Yes, known to enhance podocin-nephrin interaction by nephrin phosphorylation, diminishes beta-arrestin2-nephrin interaction. beta-Arrestin2 induces nephrin endocytosis and attenuates nephrin signaling. This finding suggests that nephrin Y1193 serves as a molecular switch that determines the integrity of the slit diaphragm by functional competition between beta-arrestin2 and podocin. This concept offers a molecular pathomechanism of slit diaphragm distortion and opens therapeutic avenues for glomerular diseases.
| S-EPMC1564064 | biostudies-literature
Project description:Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.
| S-EPMC7160243 | biostudies-literature
Project description:Mutations in acute myeloid leukemia (AML)-associated oncogenes often arise in hematopoietic stem cells (HSCs) and promote acquisition of leukemia stem cell (LSC) phenotypes. However, as LSCs often share features of lineage-restricted progenitors, the relative contribution of differentiation status to LSC transformation is unclear. Using murine MLL-AF9 and MOZ-TIF2 AML models, we show that myeloid differentiation to granulocyte macrophage progenitors (GMPs) is critical for LSC generation. Disrupting GMP formation by deleting the lineage-restricted transcription factor C/EBPa blocked normal granulocyte formation and prevented initiation of AML. However, restoring myeloid differentiation in C/EBPa mutants with inflammatory cytokines reestablished AML transformation capacity. Genomic analyses of GMPs, including gene expression and H3K79me2 profiling in conjunction with ATAC-seq, revealed a permissive genomic environment for activation of a minimal transcription program shared by GMPs and LSCs. Together, these findings show that myeloid differentiation is a prerequisite for LSC formation and AML development, providing insights for therapeutic development.
| S-EPMC4636971 | biostudies-literature
Project description:Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF-04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF-913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+ cells than CD34- cells. In vitro treatment with PF-913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF-913 attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF-913 modulated self-renewal signatures and cell cycle progression. Furthermore, PF-913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS-5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia-initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.
| S-EPMC5084664 | biostudies-literature
Project description:Hematopoietic stem cells (HSCs) engage in complex bidirectional signals with the hematopoietic microenvironment (HM), and there is emerging evidence that leukemia stem cells (LSCs) may use similar interactions. Using a syngeneic retroviral model of MLL-AF9 induced acute myeloid leukemia (AML), we have identified 2 different stages of leukemia progression, propagated by "pre-LSCs" and established leukemia (LSCs) and compared the homing properties of these distinctive entities to that of normal HSCs. The homing and microlocalization of pre-LSCs was most similar to long-term HSCs and was dependent on cell-intrinsic Wnt signaling. In contrast, the homing of established LSCs was most similar to that of committed myeloid progenitors and distinct from HSCs. Although osteoblast-derived Dickkopf-1, a potent Wnt inhibitor known to impair HSC function, dramatically impaired normal HSC localization within the bone marrow, it did not affect pre-LSCs, LSC homing, or AML development. Mechanistically, cell-intrinsic Wnt activation was observed in human and murine AML samples, explaining the independence of MLL-AF9 LSCs from niche-derived Wnt signals. These data identify differential engagement of HM associated with leukemic progression and identify an LSC niche that is physically distinct and independent of the constraints of Wnt signaling that apply to normal HSCs.
| S-EPMC3172801 | biostudies-other
Project description:BackgroundAcute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression.MethodsshRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG.ResultsWe explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients.ConclusionIn summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.
| S-EPMC8574011 | biostudies-literature
Project description:Increasing numbers of clinical cohorts have detected CCND2 mutations in acute myeloid leukemia (AML), especially in the subtype of AML with t(8;21) translocation. As known, this AML subtype is characterized by the formation of AML1-ETO fusion gene. However, AML1-ETO fusion gene alone is not sufficient to drive leukemia development, additional mutations are required for leukemogenesis. Here, we aim to investigate whether mutated CCND2 can cooperate with AML1-ETO fusion gene to drive leukemia initiation and progression. In our previous study, the conditional AML1-ETO knock-in mouse model (AML1/ETO mouse), which represented a pre-leukemia stage as myeloproliferative neoplasm phenotype, was established. To confirm whether the AML1-ETO and CCND2 mutation can cooperate to drive leukemia, the mice transduction and transplantation model harboring both AML1-ETO and CCND2 gene (both wildtype and mutant) were established. Upon the assessment of the phenotype, biological features and survival of the mice, only the mice overexpressing the AML1-ETO and CCND2 simultaneously were eventually progressed to leukemia. Besides, compared to mice overexpressing AML-ETO gene alone, mTOR and cell cycle-related pathways were significantly enriched in mice harboring both AML1-ETO and CCND2. And the selective mTOR inhibitor, Everolimus, can reduce the leukemia burden and prolong the survival of this group of mice. In conclusion, we confirmed that introduction of the CCND2 gene into the AML/ETO pre-leukemia mice can trigger the development of leukemia. We also confirmed that CCND2 overexpression resulted in the upregulation of the mTOR pathway and inhibiting the pathway may be a therapeutic agent for this subtype of leukemia.
2024-04-19 | GSE263911 | GEO
Project description:BackgroundThe primary objective was to describe infectious complications in children with acute myeloid leukemia from presentation to the healthcare system to initiation of chemotherapy and to describe how these infections differ depending on neutropenia.MethodsWe conducted a retrospective, population-based cohort study that included children and adolescents with acute myeloid leukemia diagnosed and treated at 15 Canadian centers. We evaluated infections that occurred between presentation to the healthcare system (for symptoms that led to the diagnosis of acute myeloid leukemia) until initiation of chemotherapy.ResultsAmong 328 children, 92 (28.0%) were neutropenic at presentation. Eleven (3.4%) had sterile-site microbiologically documented infection and four had bacteremia (only one Gram negative). Infection rate was not influenced by neutropenia. No child died from an infectious cause prior to chemotherapy initiation.ConclusionIt may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed acute myeloid leukemia until initiation of chemotherapy as long as they appear well without a clinical focus of infection. Future work could examine biomarkers or a clinical score to identify children presenting with leukemia and fever who are more likely to have an invasive infection.
| S-EPMC3637321 | biostudies-literature