MLL-AF9 expression in normal human umbilical cord blood CD34+ cells leads to long-term proliferation of a myeloid progenitor cell with leukemogenic potential. Expression of a Core Binding Factor leukemia fusion (AML1-ETO or CBFbeta-SMMHC) in human CD34+ cells results in self-renewal of primitive progenitor cells with multilineage potential and stem cell ability, but these cells do not induce leukemia in immunodeficient mice. This comparative microarray study was initiated to determine how faithful these cell cultures are to the transcriptome of patient samples expressing each of these different fusion proteins, and to analyze the signaling pathways that are unique to CBF cultures and MLL-fusion cultures, with the hope of determining why the MLL-fusion cells are leukemogenic while the CBF cells are not.
Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia.
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View SamplesThe Kruppel-like factor 5 (Klf5) regulates pluripotent stem cell self-renewal but its role in somatic stem cells is unknown. Klf5 deficient hematopoietic stem cells and progenitors (HSC/P) fail to engraft after transplantation. This HSC/P defect was associated with impaired bone marrow (BM) homing and lodging and decreased retention in BM. The Klf5/ HSC/P homing defect associated with decreased adhesion to fibronectin and expression of membrane-bound 1/2-integrins. In vivo inducible gain-of-function of Klf5 in HSC translated into increased HSC/P adhesion. The expression of Rab5 family members, mediators of 1/2-integrin recycling in the early endosome, was decreased in Klf5/ HSC/P. Klf5 binds directly to the promoter of Rab5a/b and overexpression of Rab5b rescued the expression of activated 1/2-integrins, adhesion and BM homing of Klf5/ HSC/P. Altogether, these data indicate that Klf5 is indispensable for adhesion, homing, lodging and retention of HSC/P in the BM through Rab5-dependent post-translational regulation of Beta1/Beta2 integrins.
Klf5 controls bone marrow homing of stem cells and progenitors through Rab5-mediated β1/β2-integrin trafficking.
Specimen part
View SamplesIn March 2006, murine Bone Marrow Stromal Cells (BMSC) were flown in the Soyuz 12S to the International Space Station to investigate the effects of microgravity on their osteogenic potential in a three-dimensional environment. BMSC were grown in porous bioceramic Skelite disks ( 9 mm x T 1.2 mm). The constructs were exposed to microgravity for ca. 8 days, then fixed for RNA extraction. While the flight experiment was performed in fully automated hardware inside the KUBIK incubator, one group of control samples were incubated inside manually operated hardwares (flight control), and the other control group was incubated under routine laboratory conditions (lab control). The altered gene expression profile was analyzed by Mouse Gene 1.0 ST array (Affymetrix) representing whole-transcript coverage. Each one of the 28853 genes is represented on the array by approximately 26 probes spread across the full length of the gene, providing a more complete and more accurate picture of gene expression than the 3 based expression array design.
Activation of nervous system development genes in bone marrow derived mesenchymal stem cells following spaceflight exposure.
Specimen part, Disease
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Specimen part, Cell line
View SamplesWe performed whole genome expression analysis using BCR/ABL expressing Kit+ cells derived from wild type and ROSACreERT2c-Fosfl/flDusp1-/- bone marrow cells. Wild type kit+ cells were treated with DFC+BCI and DFC+BC+Im to mimic the genetic loss of c-Fos and Dusp1. Overall design: The experiment was designed to test whether chemical inhibition by FOS and Dusp1 Inhibitor mimics the genetic deletion of cFOS and Dusp1 in mouse primary cells transduced with BCR-ABL. This data is part of the super series Mechanism of Oncogene addiction GSE75058.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Specimen part, Cell line, Subject
View SamplesThe Baf3 are dependent on IL-3 for grwoth however transformation by BCR -ABL oncogene causes BAf3 cells independent of IL-3. The BAf3 cells expressing BCR-ABL are dependent on continuous expression of BCR_ABL for growth. Inhibitionof BCR-ABL by its inhibitor Imatinib cause these cells to undergo apoptosis. When these cells are grown with IL-3 these cells do not respond to Imatinib mediated grwoth arrest.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Cell line
View SamplesK562 cells when grown with erythropeitin do not respond to Imatinib. Here we are comparing the gene expression profile from imatinib resistant and sensitive cells.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Cell line
View SamplesBAF3 cells harboring constitutively expressing BCR-ABL were grown with or without IL-3 supplement and treated with Imatinib and live cells from the IL-3 and without IL-3 were sorted by FACS.
Targeting c-FOS and DUSP1 abrogates intrinsic resistance to tyrosine-kinase inhibitor therapy in BCR-ABL-induced leukemia.
Cell line
View SamplesEGR3 expression is upregulated in human prostate cancer compared to normal prostate tissue and is associated with absence of relapse, while low EGR3 expression in tumors is predicitive of disease relapse (Pio et al., PLOS One 2013; 8(1):e54096). However the function of EGR3 in prostate cancer is unknown. Human prostate cancer cells M12 containing high levels of EGR3 were used for shRNA-mediated silencing of EGR3. Gene expression analysis of EGR3 knockdown cells reveals a role in inflammation and the existence of a crosstalk with the NFkB pathway.
Early growth response 3 (Egr3) is highly over-expressed in non-relapsing prostate cancer but not in relapsing prostate cancer.
Cell line, Treatment
View SamplesChromosome 5q deletions (del(5q)) are common in high-risk (HR) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR-MDS/AML and miR-146a-/- hematopoietic stem/progenitor cells (HSPC) results in TRAF6/NF- activation. Increased survival and proliferation of HSPC from miR-146alow HR-MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-B-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-B signaling, as disrupting the p62-TRAF6 signaling complex results in cell cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR-MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-B to sustain TRAF6/NF-B signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.
Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network.
Sex, Specimen part
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