Gene expression from MS5 stroma cells co-cultured with normal human hematopoietic progenitors/stem cells (HSPCs) and AML
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PROVIDER: PRJNA563916 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukemia remodels the bone marrow non-hematopoietic microenvironment which disrupts niche archiecture and normal hematopoiesis The precise interactions underlying this process are not well understood We used microarrays to detail the global programme of gene expression underlying the interactions between healthy mesenchymal stroma cells and normal hematopoietic progenitors/stem cells (HSPCs) and AML
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Project description:Severe congenital neutropenia (CN) is a pre-leukemia syndrome that, in the majority of patients, is caused by heterogeneous ELANE mutations encoding neutrophil elastase (NE). To study leukemogenesis associated with CN we generated CN and CN/AML patient-specific induced pluripotent stem cells (iPSCs). Additional mutations in leukemia-relevant genes, CSF3R and RUNX1, were introduced using CRISPR/Cas9 gene-editing. Consequently, we performed in vitro embryoid body (EB)-based hematopoietic and myeloid differentiation of generated iPSC lines. On day 14-17 of EB-based differentiation, iPSC-derived CD45+CD34+ cells were harvested and mRNA was isolated using RNeasy Mini- or Micro Kit (Qiagen). Sequencing libraries were prepared using the TruSeq RNA Sample Prep Kit (Illumina). Poly (A) selected single-read and pair-read sequencing libraries were sequenced on the Illumina platform in order to compare the transcriptomes of CN and CN/AML iPSCs-derived HSPCs from 2 CN/AML patients. Next, we identified that BAALC knockout resulted in a dramatic induction of granulocytic differentiation and a significant reduction in proliferation of CN/AML iPSC-derived HSPCs. To identify BAALC-dependent leukemia-associated gene expression, we compared the transcriptomes of CN/AML iPSCs before and after BAALC KO using a similar approach described above for CN and CN/AML iPSCs-derived HSPCs.
2021-03-08 | E-MTAB-10162 | biostudies-arrayexpress
Project description:Control group is an essential part of the research design which provide a baseline by elimating variables, bias and other factors that skew the data. Human CD34+ cells are generally used as controls to study myeloid malignancies. This study determines whether fresh or short term cytokine induced CD34+ HSPCs can provide a more appropriate normal control (compared to AML blasts) for target discovery studies. We here determine that the GEP of CD34+ cells that do not undergo ex vivo expansion best match the GEP of minimally differentiated AML blasts and would serve as a better control to identify novel targets in the AML blast population.
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Project description:The methyltransferase G9a was found to play a role in the disease progression of a murine model of AML. Mouse HSPCs were transformed with HoxA9/Meis1 and treated with G9a/GLP inhibitor UNC0638. We used microarrays to detail the global program of gene expression that depends on the methyltransferase activity of G9a in murine AML cells.
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Project description:Purpose: Stanniocalcin 1 (STC1) is a secreted glycoprotein expressed in mesenchymal stroma cells (MSCs). STC1 expression is upregulated in response to acute myeloid leukemia (AML) co-culture. Recombinant STC1 has proliferation limiting effects on human hematopoietic stem/progenitors cells (HSPCs) and facilitiates the preservation of HSCs ex vivo. We hope to gain insight into the mechanism by exploring the transcriptome of stem/progenitors exposed to STC1.
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Project description:The derivation of functional, transplantable HSCs from an pluripotent stem cells in vitro holds great promise for clinical therapies, but is unachieved. In order to achieve full functionality of HSCs, it is vital to determine the extent to which PSCs can currently be differentiated to the HSC program in vitro and identify the remaining dysregulated genetic pathways. Microarrays were used to compare the transcritomes of ESC-derived immunophenotypic HSPCs to endogenous HSPCs from various stages of development to determine the programs important for human HSC development and function, and which programs were lacking in ESC-derived hematopoietic cells. CD34+CD38-CD43+CD90+ HSPCs were sorted from human placenta and embryoid bodies, and CD34+CD38-CD45+CD90+ HSPCs sorted from fetal liver and embryoid bodies co-cultured on OP9-M2 stroma, the RNA was extracted, library created and hybridized to the Affymetrix microarray
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Project description:Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the bone marrow (BM) stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Iradubicin (standard AML chemotherapy) by interfering with the BM stroma-mediated chemoresistance. We report that lenalidomide and pomalidomide have cytotoxic effects on neither AML cells nor BM-MSCs, but they increase the immunosuppressive/immunomodulatory properties of BM-MSCs. When combined with AraC and Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide highly mobilizes AML cells, but not healthy CD34+ cells, to peripheral blood (PB) likely through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize AML blasts to PB through downregulation of CXCR4 but do not improve AraC/Idarubicin activity in a preclinical model of AML.
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Project description:ETO2 (CBFA2T3) functions as a transcriptional corepressor, which can directly bind to E-protein family of transcriptional factors. Translocation of ETO2 has been implicated in multiple leukemogenic pathways. ETO2 also plays an important role in self-renewal, proliferation, and expansion of hematopoietic stem/progenitor cells (HSPCs). Here we report the genomic binding sites of ETO2 in human cord-blood derived CD34+ HSPCs, Kasumi-1 t(8;21) AML cells, and U937 AML cells. All ChIP-Seq assays were performed with an ETO2 specific antibody that does not recognize other ETO/MTG family proteins (ETO or MTGR1).
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Project description:Haematopoietic stem and progenitor cells (HSPCs) in the foetus and adult possess distinct molecular landscapes that regulate cell fate and change their susceptibility to initiation and progression of haematopoietic malignancies. The proteomic programs that govern these differences remain elusive. In this study, we have utilized a mass spectrometry-based quantitative proteomics approach to comprehensively describe and compare the proteome of foetal and adult HSPCs. We found that the proteome of foetal HSPCs is relatively simple, characterized by proteins involved in cell cycle and cell proliferation, while their adult counterparts are defined by a larger set of proteins that are involved in more diverse cellular processes. These adult characteristics include an arsenal of proteins important for viral and bacterial defence, as well as protection against ROS-induced protein oxidation. Our further analyses of Type I interferon signalling shows that foetal HSPCs are sensitive to Interferon a (IFNa), which impairs their production of mature lymphoid cells, whereas stimulation with IFNa to the pregnant mother enhances the production of early progenitors from foetal HSCs. Our results provide new and important insights into the molecular landscape of foetal and adult haematopoiesis that advance our understanding of normal and malignant haematopoiesis during foetal and adult life.
2017-12-12 | PXD006876 | Pride