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Project description:We used a positron emission tomography (PET) tracer 18F fluorodeoxyglucose ([18F]-FDG) and transcriptomic analysis to detect glucose uptake by cells in the bone marrow micro-environment with an MLL-AF9-induced mouse model. Leukaemic cells had the greatest glucose uptake. To determine whether glucose uptake is driven by intrinsic demand, we applied RNA-seq of sorted leukaemia cells (GFP+) and bone marrow micro-environment myeloid cells (GFP-CD11b+) from the MLL-AF9 transduced mouse model.
2023-04-14 | GSE227581 | GEO
Project description:To identify the metabolic transcriptome landscape within leukaemic cells we performed scRNA-Seq on the sorted leukaemia cells (GFP+) cells from MLL-AF9 mice.
2023-04-14 | GSE227583 | GEO
Project description:Leukaemia progressively invades bone marrow (BM), outcompeting healthy haematopoiesis by mechanisms that are not fully understood. Combining cell number measurements with a short-timescale dual pulse labelling method, we simultaneously determine the proliferation dynamics of primitive haematopoietic compartments and acute myeloid leukaemia (AML). We observe an unchanging proportion of AML cells entering S phase per hour throughout disease progression, with substantial BM egress at high levels of infiltration. For healthy haematopoiesis, we find haematopoietic stem cells (HSCs) make a significant contribution to cell production, but we phenotypically identify a quiescent subpopulation with enhanced engraftment ability. During AML progression, we observe that multipotent progenitors maintain a constant proportion entering S phase per hour, despite a dramatic decrease in the overall population size. Primitive populations are lost from BM with kinetics that are consistent with ousting irrespective of cell cycle state, with the exception of the quiescent HSC subpopulation, which is more resistant to elimination.
| S-EPMC5802720 | biostudies-literature
Project description:About 5-10% newly diagnosed and about 20-30% of relapsed acute promyelocytic leukemia (APL) patients will have disease recurrence after receiving currently accepted standards of care. While there are reports of micro-environment mediated drug resistance (EM-DR) in AML, there is no data on the effect of malignant promyelocyte and stromal interaction on Arsenic trioxide (ATO) induced apoptosis. We undertook a preliminary study to evaluate the role of EM-DR to ATO in APL. In direct co-culture (contact dependent system) of malignant promyelocyte with stromal cells, the stromal cells gave a significant protective effect against ATO at different concentrations used (1 to 8 μmol; NB4 (APL cell line) In a gene expression profiling comparing NB4 cells in co-culture with NB4 cells alone, 1846 genes were differentially regulated. On a preliminary analysis, we observed an up-regulation of various pathways such as adhesion (ITGB1, ITGB2, ITGB7, etc.), Cytokines (IL-6, IL-8, IL-18, CCL2, CCL10, etc.) Wnt signalling (Wnt5a, Wnt11, NFATC4, etc,) NF-kB pathway (ICAM1, BIRC2, BIRC3, XIAP1, etc.) in the leukemic cells. The NF-kB pathway has been validated using real time PCR which correlated with the genes being differentially regulated in NB4 cells co-cultured in stroma. Agilent one-color experiment,Organism: Homo sapiens ,Custom Agilent 8x60k Human Whole Genome Microarray Gene expression (AMADID: 039494) , Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)
2016-09-01 | E-GEOD-73157 | biostudies-arrayexpress
Project description:About 5-10% newly diagnosed and about 20-30% of relapsed acute promyelocytic leukemia (APL) patients will have disease recurrence after receiving currently accepted standards of care. While there are reports of micro-environment mediated drug resistance (EM-DR) in AML, there is no data on the effect of malignant promyelocyte and stromal interaction on Arsenic trioxide (ATO) induced apoptosis. We undertook a preliminary study to evaluate the role of EM-DR to ATO in APL. In direct co-culture (contact dependent system) of malignant promyelocyte with stromal cells, the stromal cells gave a significant protective effect against ATO at different concentrations used (1 to 8 μmol; NB4 (APL cell line) In a gene expression profiling comparing NB4 cells in co-culture with NB4 cells alone, 1846 genes were differentially regulated. On a preliminary analysis, we observed an up-regulation of various pathways such as adhesion (ITGB1, ITGB2, ITGB7, etc.), Cytokines (IL-6, IL-8, IL-18, CCL2, CCL10, etc.) Wnt signalling (Wnt5a, Wnt11, NFATC4, etc,) NF-kB pathway (ICAM1, BIRC2, BIRC3, XIAP1, etc.) in the leukemic cells. The NF-kB pathway has been validated using real time PCR which correlated with the genes being differentially regulated in NB4 cells co-cultured in stroma.
2016-09-01 | GSE73157 | GEO
Project description:Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
| S-EPMC9820412 | biostudies-literature
Project description:Acute myeloid leukaemia (AML) creates an immunosuppressive environment to conventional T cells through Arginase 2 (ARG2)-induced arginine depletion. We identify that AML blasts release the acute phase protein serum amyloid A (SAA), which acts in an autocrine manner to upregulate ARG2 expression and activity, and promote AML blast viability. Following in vitro cross-talk invariant natural killer T (iNKT) cells become activated, upregulate mitochondrial capacity, and release IFN-γ. iNKT retain their ability to proliferate and be activated despite the low arginine AML environment, due to the upregulation of Large Neutral Amino Acid Transporter-1 (LAT-1) and Argininosuccinate Synthetase 1 (ASS)-dependent amino acid pathways, resulting in AML cell death. T cell proliferation is restored in vitro and in vivo. The capacity of iNKT cells to restore antigen-specific T cell immunity was similarly demonstrated against myeloid-derived suppressor cells (MDSCs) in wild-type and Jα18-/- syngeneic lymphoma-bearing models in vivo. Thus, stimulation of iNKT cell activity has the potential as an immunotherapy against AML or as an adjunct to boost antigen-specific T cell immunotherapies in haematological or solid cancers.
| S-EPMC9947083 | biostudies-literature
Project description: Not available
| S-EPMC4755922 | biostudies-literature
Project description:It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells.
| S-EPMC5164929 | biostudies-literature
Project description:In addition to their roles in different biological processes, microRNAs in the tumor microenvironment appear to be potential diagnostic and prognostic biomarkers for various malignant diseases, including acute myeloid leukemia (AML). To date, no screening of circulating miRNAs has been carried out in the bone marrow compartment of AML. Accordingly, we investigated the circulating miRNA profile in AML bone marrow at diagnosis (AMLD) and first complete remission post treatment (AMLPT) in comparison to healthy donors (HD). Circulating miRNAs were isolated from AML bone marrow aspirations, and a low-density TaqMan miRNA array was performed to identify deregulated miRNAs followed by quantitative RT-PCR to validate the results. Bioinformatic analysis was conducted to evaluate the diagnostic and prognostic accuracy of the highly and significantly identified deregulated miRNA(s) as potential candidate biomarker(s). We found several deregulated miRNAs between the AMLD vs. HD vs. AMLPT groups, which were involved in tumor progression and immune suppression pathways. We also identified significant diagnostic and prognostic signatures with the ability to predict AML patient treatment response. This study provides a possible role of enriched circulating bone marrow miRNAs in the initiation and progression of AML and highlights new markers for prognosis and treatment monitoring.
| S-EPMC7583041 | biostudies-literature