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GSE42253
Homo sapiens
6 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hsp90 is critical for regulation of the phenotype and functional activity of human T lymphocytes and natural killer (NK) cells.
Publication Title
Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.
Publication Title
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 2 Downloadable Samples
Illumina Genome Analyzer IIx
Description
Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow (BM) microenvironment might contribute to the clinical outcomes of this common event. We previously showed that BM nestin+ mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin+ MSCs are consistently reduced in the BM of MPN patients and mice expressing the human JAK2V617F mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by BM neural damage and Schwann cell death triggered by interleukin-1b produced by mutant HSCs. In turn, in vivo depletion of nestin+ cells or their production of CXCL12 expanded mutant HSCs and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with b3-adrenergic agonists that restored the sympathetic regulation of nestin+ MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing leukaemic stem cells. Our results demonstrate that mutant HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets. Overall design: CD45- CD31- Ter119- GFP+ cells were sorted from the BM of Nes-gfp;Mx1-cre;JAK2-V617F mice and control littermates 6 weeks after pIpC treatment and were subjected to RNA sequencing. Each sample was pooled from 3 animals of the same genotype.
Publication Title
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
In this study we analyzed the behavior of bone marrow MSC (BM-MSC) from MPN patients with the mutation in JAK2V617F. We initially characterized the biological function and gene expression profile changes in BM-MSC from MPN patients when compared to BM-MSC of healthy donors (HD). Then, we established co-cultures between MSC cell lines (HTERT and HS5) and the UKE-1 MPN cell line, and performed RT-PCR to study if the leukemic cells were able to modify the genes related to hematopoietic support.
Publication Title
Mesenchymal stromal cells (MSC) from JAK2+ myeloproliferative neoplasms differ from normal MSC and contribute to the maintenance of neoplastic hematopoiesis.
Sample Metadata Fields
Specimen part, Disease stage, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2000
Description
The purpose of this study is to investigate the transcriptional programs as it relates to disease latency initiated by different MLL fusion proteins, including: MLL-AF1p, MLL-AF6, MLL-Gas7, MLL-AF9 and MLL-ENL. Leukemia cell lines were established by transforming kit+ mouse bone marrow cells with retroviruses coding MLL-AF1p, MLL-AF6, MLL-Gas7, MLL-AF9 or MLL-ENL. At early phase after the cell lines were established, cells growing at exponential phase (cell density at 0.5~1x106/ml) were harvested for RNA extraction and sequencing purpose. Overall design: Sequencing is performed on total RNA isolated from mouse leukemia cell lines generated from kit+ mouse bone marrow cells transduced with various MLL fusion proteins and is compared to control total RNA isolated from kit+ mouse bone marrow cells.
Publication Title
Differential regulation of the c-Myc/Lin28 axis discriminates subclasses of rearranged MLL leukemia.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
RNAseq characterization of gene expression changes 72 hours after genomic excision of Cebpa in murine hematopoietic progenitors from Cebpaf/f;CreER mice transformed by Hoxa9/Meis1. In the presence of tamoxifen (4OHT), Cre-ER localizes to the nucleus of cells allowing for excision of Cebpa and loss of C/EBPa protein levels. Loss of C/EBPa leads to a decrease in cellular proliferation. Overall design: Examination of gene expression by RNAseq in two conditions in biological replicates.
Publication Title
C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2000
Description
Characterization of gene expression changes 72 hours after withdrawal of tamoxifen in murine hematopoietic progenitors transformed by Hoxa9-ER/Meis1 using RNAseq. In the presence of tamoxifen (4OHT), Hoxa9-ER localizes to the nucleus of cells allowing for transformation, while withdrawal of 4OHT (culture in EtOH) leads to loss of nuclear Hoxa9-ER. Loss of Hoxa9-ER leads to a decrease in cellular proliferation and differentiation along the myeloid lineage. Overall design: Examination of gene expression by RNAseq in two conditions in biological replicates.
Publication Title
C/EBPα is an essential collaborator in Hoxa9/Meis1-mediated leukemogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Importantly increasing evidence shows that Hox genes such as Hoxa9 are key regulators of stem cell self-renewal and hematopoiesis. Hoxa9 is expressed in early hematopoietic progenitor cells and promotes stem cell expansion. In contrast Hoxa9 down regulation is associated with hematopoietic differentiation. In addition to its role in development, HOXA9 has been intensively studied because of its central role in human acute leukemias. Despite their obvious biomedical importance, the mechanisms through which Hoxa9 and its partner proteins exert their downstream functions are poorly understood.
Publication Title
The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis.
Sample Metadata Fields
Sex, Specimen part, Cell line, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
The Polymerase Associated Factor (PAFc) complex is an epigenetic regulating complex that has been shown to to be important for Acute Myeloid Leukemias harboring an MLL chromosomal translocations, such as MLL-AF9 leukemias. This study describes the transcriptomic profiling of AML cells following genetic deletion of the PAFc subunit Cdc73. Overall design: Cdc73floxed cells were transformed to an AML using MLL-AF9 oncogene transduction. The cells were also transduced with a 4OHT inducible CreER. The cells were then treated for 24 or 48 hours with 4OHT to induce genetic excision of Cdc73 and polyA mRNA was isolated for sequencing of the transcriptome. Biological duplicates are labelled _1 and _2.
Publication Title
The PAF complex regulation of Prmt5 facilitates the progression and maintenance of MLL fusion leukemia.
Sample Metadata Fields
Cell line, Treatment, Subject, Time
View Samples