Mutational Screening of Human Acute Myleloid Leukaemia Samples
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ABSTRACT:
PROVIDER: EGAS00001000046 | EGA |
REPOSITORIES: EGA
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Project description:The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate11,12. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mutAML. Gene sets characteristic for IDHmut AML13 were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1highAML showed robust enrichment for leukaemia stem-cell signatures14,15, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA–BCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.
2020-02-21 | PXD008307 | Pride
Project description:Acute Myeloid Leukaemia (AML) carries a 5 year survival rate of just 24%. Toxic chemotherapy regimens remain the backbone of standard of care for AML. The FLT3 tyrosine kinase is a recognised AML oncogene, with FLT3 activating mutations occurring in approximately one third of all AML patients. However, therapeutic targeting of FLT3 has proven difficult as monotherapy, with the development of drug resistance and relapse. Characterisation of the signalling pathways regulated by mutant FLT3 is required to identify better therapeutic strategies.
2019-12-20 | MSV000084730 | MassIVE
Project description:Background: Acute lymphoblastic leukaemia (ALL) is the most common cancer in children. Proteomics, supported by mass spectrometry and bioinformatics, investigates cancer biology and contributes to translational research.
Purpose of the study: To identify the plasma proteome profile of children across different risk groups of ALL. Neurexophilin and PC-esterase family, member 3 (NXPE3), was validated. The protein-protein interactions (PPI) of NXPE3 were evaluated with bioinformatics analyses.
Material and methods: Plasma samples from 15 patients with B-ALL standard risk (SR), B-ALL high risk (HR), and T-ALL high risk (HR), were analyzed using liquid chromatography with tandem mass spectrometry. NXPE3 protein was validated using ELISA. To compare the NXPE3 values across groups, the Kruskal-Wallis test was applied. A p-value < 0.05 was considered significant. STRING database was used for PPI.
2025-12-12 | MSV000100202 | MassIVE
Project description:Acute myeloid leukemia (AML) is a disease with poor outcome but patients harbouring certain chromosomal rearrangements or complex karyotypes have particularly adverse prognosis. For these patients, targeted therapies have not yet made a significant clinical impact. To understand the molecular landscape of poor risk AML we profiled 55 poor risk AML patients using a multiomics approach that included transcriptomics (n=39), proteomics (n=55), phosphoproteomics (n=55) and an ex vivo drug sensitivity screening (482 compounds tested in at least 30 patients). We identified a phosphoproteomics signature that define two biologically distinct groups of KMT2A rearranged leukaemia, which we term MLLGA and MLLGB. MLLGA presented increased DOT1L phosphorylation, HOXA gene expression, CDK1 activity and phosphorylation of proteins involved in RNA metabolism, replication and DNA damage when compared to MLLGB and no KMT2A rearranged samples. MLLGA was particularly sensitive to 15 compounds including genotoxic drugs and inhibitors of mitotic kinases and IMPDH relative to other cases. The expression of IMPDH2 and multiple nucleolar proteins was higher in MLLGA and correlated with the response to IMPDH inhibition in KMT2A rearranged leukaemia, suggesting a role of the nucleolar activity in sensitivity to IMPDH inhibition. In summary, our multilayer molecular profiling of poor risk AML matched to the response to hundreds of compounds identified a phosphoproteomics signature that define two biologically and phenotypically distinct groups of KMT2A rearranged leukaemia. These data provide a rationale for the development of specific therapies for KMT2A subgroups characterised by the MLLGA phosphoproteomics signature identified in this study.
2023-03-11 | PXD032980 | Pride
Project description:The t(8;21) Acute Myeloid Leukaemia (AML) Kasumi-1cell line with N822K KIT mutation, is a model system for leukemogenesis. As AML initiating cells reside in the CD34+CD38- fraction, we addressed the refined cytogenomic characterization and miRNA expression of Kasumi-1 cell line and its FACS-sorted subpopulations focussing on this compartment. By conventional cytogenetics, Spectral Karyotyping and array-CGH the cytogenomic profile of Kasumi-1 cells evidenced only subtle regions differentially represented in CD34+CD38- cells. Expression profiling by a miRNA platform showed a set of miRNA differentially expressed in paired subpopulations and the signature of miR-584 and miR-182 upregulation in the CD34+CD38- fraction.
2010-02-19 | E-TABM-909 | biostudies-arrayexpress
Project description:Characterization of the transcriptional changes occurring at the single-cell level during the progression of a chronic lymphoid leukaemia treated with Rituximab, Fludarabine and Cyclophosphamide.
2020-10-27 | GSE150930 | GEO
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE260919 | GEO
Project description:Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and potential therapeutic interventions.
2024-08-08 | GSE224643 | GEO
Project description:Single-cell RNA-sequencing of mouse fibroblasts for the identification and functional characterization of non-coding RNAs. Non-coding RNAs were assigned putative functions based on single-cell expression patters, e.g. phase specific expression during the cell cycle. Additionally, allele-level resolution was used to characterize coordinated and mutually exclusive expressions of noncoding RNAs against nearby protein coding genes.
2018-12-19 | E-MTAB-6385 | biostudies-arrayexpress
Project description:Immunological classifiers that predict patient outcome and therapeutic responses have been constructed through targeted immune gene expression profiling of diagnostic bone marrow samples from patients with acute myeloid leukaemia.
2022-09-16 | GSE176100 | GEO