Metabolomic and 13C-glucose isotopic profiling data of MOLM14 AML cell line treated with venetoclax, cytarabine or combo and shBCL2.
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ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive Plus
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Xiaoyang Su Jean-Emmanuel Sarry
PROVIDER: MSV000087892 | MassIVE | Tue Jul 27 13:16:00 BST 2021
REPOSITORIES: MassIVE
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Project description:We performed quantitative metabolomics and 13C-glucose isotopic profiling experiments on AML MOLM14 cell line following 24h of treatment with venetoclax (50 nM) and aracytine (25 uM) or combination compared to untreated samples. In addition, we also performed quantitative metabolomic experiments on MOLM14 silenced for BCL2 (shRNA).
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2018-06-01 | GSE114109 | GEO
Project description:The paper describes a model of acute myeloid leukaemia.
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This model is described in the article:
Optimal control of acute myeloid leukaemia
Jesse A. Sharp, Alexander P Browning, Tarunendu Mapder, Kevin Burrage, Matthew J Simpson
Journal of Theoretical Biology 470 (2019) 30–42
Abstract:
Acute myeloid leukaemia (AML) is a blood cancer affecting haematopoietic stem cells. AML is routinely treated with chemotherapy, and so it is of great interest to develop optimal chemotherapy treatment strategies. In this work, we incorporate an immune response into a stem cell model of AML, since we find that previous models lacking an immune response are inappropriate for deriving optimal control strategies. Using optimal control theory, we produce continuous controls and bang-bang controls, corre- sponding to a range of objectives and parameter choices. Through example calculations, we provide a practical approach to applying optimal control using Pontryagin’s Maximum Principle. In particular, we describe and explore factors that have a profound influence on numerical convergence. We find that the convergence behaviour is sensitive to the method of control updating, the nature of the control, and to the relative weighting of terms in the objective function. All codes we use to implement optimal control are made available.
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Project description:MIR139 is a critical tumor suppressor and commonly silenced in human cancer, including acute myeloid leukemia (AML). Here, we found that depletion of identified MIR139 targets affects AML outgrowth. We unraveled the mechanism of MIR139 gene inactivation in AML expressing the Mixed-Lineage Leukemia (MLL)-AF9 oncogene. Epigenetic analyses revealed two well-conserved putative enhancer regions in close proximity of transcriptional start sites (TSS) of MIR139. These regions were silenced by the Polycomb-Repressive Complex-2 (PRC2) downstream of MLL-AF9. Genomic deletion of these regions abolished MIR139 transcriptional regulation in normal and oncogenic conditions. Genome-wide knockout screens revealed the transcriptional pausing factor of RNA Polymerase-II, POLR2M, as a critical MIR139-silencing factor. Furthermore, direct POLR2M binding to the MIR139 TSS induced paused transcription, which was abrogated upon PRC2 inhibition. We present evidence for an oncogenic POLR2M-mediated MIR139 silencing mechanism, downstream of MLL-AF9 and PRC2. Together, our findings highlight the importance of POLR2M-mediated paused transcription in AML.
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Project description:We report the pro-leukemic activities of PRMT5 in AML partly via modulating the transcription of key genes. The goal of this experiment is to confirm the changes observed in expression of genes targeted by PRMT5 activities. RNA Deep sequencing was employed to validate and reproduce the changes measured by quantitative reverse transcription polymerase chain reaction (qRTâPCR) techniques. Total RNA samples from MV4-11 cell line (FLT3-ITD AML) following PRMT5 knockdown using specific short hairpin RNA (shRNA) was used to compare gene expression pattern between PRMT5/Knockdown and control (control: MV4-11 cells transduced with scramble control).
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Project description:This SuperSeries is composed of the following subset Series: GSE30745: Expression data from murine acute myeloid leukemia (AML) cells following shRNA-mediated suppression of Myb GSE30746: Expression data from murine Tet-off MLL-AF9/Ras acute myeloid leukemia cell lines following withdrawal of MLL-AF9 Refer to individual Series
2011-08-04 | E-GEOD-30747 | biostudies-arrayexpress
Project description:Using an integrative approach combining a Tet-off conditional AML mouse model, global expression profiling following suppression of the driving MLL-AF9 oncogene, and a new Tet-on conditional shRNA expression system we have identified Myb as critical mediator of addiction to MLL-AF9. Suppression of Myb in established AML in vivo terminates aberrant self-renewal and triggers a terminal myeloid differentiation program that precisely phenocopies the effects of suppressing MLL-AF9. Remarkably, suppressing Myb effectively eradicates aggressive and chemotherapy resistant AML. To further investigate Myb dependent transcriptional programs involved in mediating aberrant self-renewal in leukemia, we globally surveyed gene expression changes following acute shRNA-induced suppression of Myb in an established Tet-on competent model of MLL-AF9;NrasG12D-induced AML. To enable regulatable suppression of Myb in AML, we retrovirally transduced established Tet-on competent MLL-AF9;NrasG12D induced AML cells with TRMPV-Neo vectors (Zuber et al., Nature Biotech, 2010) harboring shRNAs targeting Myb (shMyb.2572 and shMyb.2652), a control shRNA targeting Renilla Luciferase (shRen.713), or an empty miR30 cassette of the recipient cloning vector (Rec). Following drug selection, shRNA expression was induced by doxycycline treatment and total RNA was isolated from sorted shRNA expressing (Venus+/dsRed+) leukemia cells after 3 days of dox treatment, and subjected to Affymetrix microarray expression analysis. Expression profiles following expression of two independent Myb shRNAs were compared to those observed after induction in shRen.713- and Rec-expressing control samples (each in 3 biological replicates).
2011-08-04 | E-GEOD-30745 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies including FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. MOLM-14 is a human FLT3-ITD AML cell line that was transduced with control (scrambled) or anti-Pim2 shRNA using lentivirus. Expression of hairpins was induced by doxycycline during 3 days and the experiments were done in biological triplicates. One million of MOLM-14 shSCR or shPim2 cells were lysed in 200µl lysis buffer (50 mM Tris (pH 8.5), 2% SDS, 20 mM TCEP, 50 mM chloroacetamide) and heated 5 min at 95°C. Proteins (50µg) from whole cell lysate were trypsin-digested overnight using the filtered-aided sample preparation (FASP) method. Liquid chromatography and mass spectrometry analyses were performed on anU3000 RSLC nanoflow-HPLC system coupled to a Q-Exactive Orbitrap mass spectrometer (both from Thermo Fisher Scientific). The analyses of raw data were performed by LFQ on Maxquant software with a maximum of 1% FDR and match between runs enabled within a 0.7 min match time window and 20 min alignment time window. Maxquant LFQ data were analyzed with Perseus, Ingenuity and Excel softwares.
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Project description:Epigenetic deregulation plays a critical role in the pathogenesis of Acute Myeloid Leukemia. But changes in histone modification patterns at the epigenome level still remain largely unknown. Here, we analyzed alterations of histone H3 acetylation patterns in a large number of patients with AML compared to CD34+ progenitor cells. Using ChIP-Chip assays, we demonstrate that AML blasts exhibit significant changes in Histone H3 acetylation levels at more than 1000 genomic loci. Importantly, at core promoter regions losses of H3 acetlyation levels prevailed which suggested that a large number of genes is epigenetically silenced in AML. The validation of identified genes led to the discovery of Peroxiredoxin 2 (PRDX2) as a potential tumor suppressor gene in AML. Peroxiredoxin-2 (PRDX2) was silenced in most AML patients by decreased Histone H3 acetylation and in almost 20% by promoter DNA hypermethylation. Low protein expression of the antioxidant PRDX2 gene was clinically associated with a poor prognosis in AML patients. Functionally, PRDX2 acted as an inhibitor of myeloid cell growth by reducing levels of reactive oxygen species generated in response to cytokines. A high level of PRDX2 expression inhibited myc-induced murine leukemogenesis whereas loss of PRDX2 increased myeloid cell proliferation and accelerated myc-induced leukemogenesis. Taken together, we identify widespread loss of Histone H3 acetylation at core promoter regions as a signature of AML blasts. Epigenome wide analyses of histone H3 acetylation led to the identification of PRDX2 as an epigenetically silenced growth suppressor that contributed to the malignant phenotype in AML. Blasts from patients with AML (n=72) were obtained at the time of diagnosis (in a few cases at first relapse). CD34+ progenitor cells (n=17) and white blood cells (n=16) were used as control samples. Immunoprecipitations were performed for anti-acetylated Histone H3. Chromatin-IPs were amplified using ligation mediated PCR and labeled using Cy3 coupled to incorporated amino-allyl-UTP. Common reference DNA consisting of a mixture of genomic DNA from AML patients was prepared, amplified and labeled in a similar way with Cy5.
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