Similar Datasets
Project description:Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis.
2023-08-11 | GSE220133 | GEO
Project description:Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by uncontrolled expansion of malignant blasts. The current treatment for AML patients includes intensive chemotherapy and high-risk hematopoietic stem cell transplantation, highlighting the need for less toxic and more effective therapies. Altered metabolism and dysregulated microRNA (miRNA) expression profiles are characteristic of AML. However, there is a paucity of studies exploring how changes in the metabolic state of the leukemic cells regulate miRNA expression leading to altered cellular behavior. Here, we blocked pyruvate entry into mitochondria by deleting the Mitochondria Pyruvate Carrier (MPC1) gene in MV4-11 and Molm-14 human AML cell lines, which decreased Oxidative Phosphorylation (OXPHOS). The loss of MPC1 led to increased expression of miR-1 in both human AML cell lines tested. AML patient sample analysis showed that higher miR-1 expression correlates with reduced survival. Transcriptional and metabolic profiling of miR-1 overexpressing AML cells revealed that miR-1 increased OXPHOS, along with key metabolites that fuel the TCA cycle such as glutamine and fumaric acid. Inhibition of glutaminolysis decreased the elevated OXPHOS in miR-1 overexpressing MV4-11 cells, highlighting that miR-1 regulates OXPHOS through glutaminolysis. Further, the overexpression of miR-1 in AML cells exacerbated disease in a mouse xenograft model. Our work expands current knowledge within the field by uncovering novel connections between AML cell metabolism and miRNA expression that facilitates disease progression. Together, our work points to miR-1 as a potential new therapeutic target that can be used to disrupt AML cell metabolism and thus pathogenesis.
2023-08-11 | GSE220126 | GEO
Project description:miRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation [miRNA]
| PRJNA908842 | ENA
Project description:miRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation
| PRJNA908841 | ENA
Project description:miRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation [mRNA]
| PRJNA908836 | ENA
Project description:MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, are involved in many complex cellular processes. Several miRNAs are differentially expressed in hematopoietic tissues and play important roles in normal differentiation, but, when aberrantly regulated, contribute to the abnormal proliferation and differentiation of leukemic cells. Recently, we reported that a small subset of miRNAs is differentially expressed in acute promyelocytic leukemia (APL) blasts and is modulated by treatment with all-trans-retinoic acid (ATRA). In particular, PML/RAR?-positive blasts from APL patients display lower levels of miRNA let-7c, a member of the let-7 family, than normal promyelocytes and its expression increases after ATRA treatment. In this study, we investigated the effects of let-7c in acute myeloid leukemia (AML) cells. We found that ectopic expression of let-7c promotes granulocytic differentiation of AML cell lines and primary blasts. Moreover, we identified PBX2, a well-known homeodomain protein whose aberrant expression enhances HoxA9-dependent leukemogenesis, as a novel let-7c target that may contribute to the AML phenotype. Together, these studies raise the possibility that perturbation of the let-7c-PBX2 pathway may have a therapeutic value in AML.
| S-EPMC7228025 | biostudies-literature
Project description:Acute myeloid leukemia (AML) arises from a complex sequence of biological and finely orchestrated events that are still poorly understood. Increasingly, epigenetic studies are providing exciting findings that may be exploited in promising and personalized cutting-edge therapies. A more appropriate and broader screening of possible players in cancer could identify a master molecular mechanism in AML. Here, we build on our previously published study by evaluating a histone deacetylase (HDAC)2-mediated miRNA regulatory network in U937 leukemic cells. Following a comparative miRNA profiling analysis in genetically and enzymatically HDAC2-downregulated AML cells, we identified miR-96-5p and miR-92a-3p as potential regulators in AML etiopathology by targeting defined genes. Our findings support the potentially beneficial role of alternative physiopathological interventions.
| S-EPMC6790563 | biostudies-literature
Project description:Mutations that activate the fms-like tyrosine kinase 3 (FLT3) receptor are among the most prevalent mutations in acute myeloid leukemias. The oncogenic role of FLT3 mutants has been attributed to the abnormal activation of several downstream signaling pathways, such as STAT3, STAT5, ERK1/2, and AKT. Here, we discovered that the cyclin-dependent kinase 1 (CDK1) pathway is also affected by internal tandem duplication mutations in FLT3. Moreover, we also identified C/EBP?, a granulopoiesis-promoting transcription factor, as a substrate for CDK1. We further demonstrated that CDK1 phosphorylates C/EBP? on serine 21, which inhibits its differentiation-inducing function. Importantly, we found that inhibition of CDK1 activity relieves the differentiation block in cell lines with mutated FLT3 as well as in primary patient-derived peripheral blood samples. Clinical trials with CDK1 inhibitors are currently under way for various malignancies. Our data strongly suggest that targeting the CDK1 pathway might be applied in the treatment of FLT3ITD mutant leukemias, especially those resistant to FLT3 inhibitor therapies.
| S-EPMC3408728 | biostudies-literature
Project description:The cancer metabolic reprogramming allows the maintenance of tumor proliferation, expansion and survival by altering key bioenergetics, biosynthetic and redox functions to meet the higher demands of tumor cells. In addition, several metabolites are also needed to perform signaling functions that further promote tumor growth and progression. These metabolic alterations have been exploited in different cancers, including acute myeloid leukemia, as novel therapeutic strategies both in preclinical models and clinical trials. Here, we review the complexity of acute myeloid leukemia (AML) metabolism and discuss how therapies targeting different aspects of cellular metabolism have demonstrated efficacy and how they provide a therapeutic window that should be explored to target the metabolic requirements of AML cells.
| S-EPMC6770240 | biostudies-literature
Project description:Acute myeloid leukemia is a clinically and genetically heterogenous disease characterized by bone marrow infiltration with immature leukemic blasts that cause bone marrow failure. Patient age, comorbidities and genomic disease characteristics have a profound impact on patient outcome. Here, we present an integrated Multi-Omics analysis of protein and gene expression as well as cytogenetics and mutations to capture the rewiring of intracellular protein networks that is most likely caused by genomic aberrations. Because protein networks are downstream of genomic aberrations, we hypothesized that our Multi-Omics approach may add to the current AML classification by identifying proteomic AML subtypes with specific clinical and molecular features that could identify therapeutic vulnerabilities and aid in the identification of predictive biomarkers.
2022-03-08 | PXD023090 | Pride