Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms
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ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: LORENA ARRANZ
PROVIDER: E-GEOD-55802 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project 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. Total RNA was isolated from BM CD45- CD31- Ter119- Nes-GFP+ cells obtained from Nes-gfp mice 10 weeks after transplantation with Mx1-cre;JAK2-V617F (n=3) or control cells (n=1). RNA was amplified using the NuGen Ovation system and hybridized to the Affymetrix MoGene 1.0 ST array.
2014-03-12 | E-GEOD-55801 | biostudies-arrayexpress
Project description:Expression of meningioma 1 (MN1) has been proposed to be a negative prognostic molecular marker in adult AML with normal cytogenetics, however its role in pediatric leukemia is unknown. We found elevated MN1 expression in 53 of 88 pediatric leukemia cases: significant amounts of MN1 were found in immature B-cell ALL and most cases of infant leukemia but no MN1 expression was detected in T-cell acute lymphoblastic leukemia (T-ALL). Interestingly 17 of 19 cases harboring MLL-X fusions showed also elevated MN1 expression. Lentiviral siRNA mediated MN1 knock-down resulted in cell cycle arrest and impaired clonogenic growth of 3 MLL-X-positive human leukemia cell lines overexpressing MN1 (THP-1, RS4;11, MOLM13). In a mouse MLL/ENL-induced leukemia MN1 overexpression resulted from retroviral provirus insertion. Strikingly co-expression of MN1 with MLL/ENL resulted in significantly reduced latency for induction of an AML phenotype in mice suggesting functional cooperation. MN1 overexpression in MLL/ENL-carrying cells resulted in expansion of the L-GMP population and facilitated disease induction in secondary recipients. Gene expression profiling allowed to define a number of potential MN1 hematopoietic targets. Up-regulation of CD34, FLT3, HLF, or DLK1 was validated in bone marrow transiently overexpressing MN1, in MN1-induced mouse leukemias, as well as in some cases of pediatric leukemias overexpressing MN1. Taken together, our work suggests that MN1 overexpression is essential for growth of leukemic cells, and that MN1 can act as a cooperating oncogene with MLL-X fusion genes most probably through modification of a distinct gene expression program that leads to expansion of a leukemia initiating cell population. In three independent experiments bone marrow cells were transduced with MSCV-MN1-IRES/YFP or empty vector. 72h after transduction EYFP-positive cells were FACS-sorted and RNA isolated by ion-exchange chromatography with RNAmini (Qiagen) according to the manufacturerâs protocol
2010-04-08 | E-GEOD-13189 | biostudies-arrayexpress
Project description:Objective: An intronic GGGGCC-repeat expansion of C9ORF72 is the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The mechanism of neurodegeneration is unknown, but a direct effect on RNA processing mediated by RNA foci transcribed from the repeat sequence has been proposed. Results: Gene level analysis revealed a number of differentially expressed networks and both cell types exhibited dysregulation of a network functionally enriched for genes encoding ‘RNA splicing’ proteins. There was a significant overlap of these genes with an independently generated list of GGGGCC-repeat protein binding partners. At the exon level, in lymphoblastoid cells derived from C9ORF72-ALS patients splicing consistency was lower than in lines derived from non-C9ORF72 ALS patients or controls; furthermore splicing consistency was lower in samples derived from patients with faster disease progression. Frequency of sense RNA foci showed a trend towards being higher in lymphoblastoid cells derived from patients with shorter survival, but there was no detectable correlation between disease severity and DNA expansion length. Significance: Up-regulation of genes encoding predicted binding partners of the C9ORF72 expansion is consistent with an attempted compensation for sequestration of these proteins. A number of studies have analysed changes in the transcriptome caused by C9ORF72 expansion, but to date findings have been inconsistent. As a potential explanation we suggest that dynamic sequestration of RNA processing proteins by RNA foci might lead to a loss of splicing consistency; indeed in our samples measurement of splicing consistency correlates with disease severity. Gene expression profiling utilised total RNA extracted from motor neurons derived from human ALS patients with an expansion of C9ORF72 (n=8), and controls (n=3).
2015-05-08 | E-GEOD-68605 | biostudies-arrayexpress
Project description:Gene expression profiling has been performed previously on motor cortex and spinal cord homogenates and of sporadic ALS cases and controls, to identify genes and pathways differentially expressed in ALS. More recent studies have combined the use of laser capture microdissection (LCM) with gene expression profiling to isolate the motor neurons from the surrounding cells, such as microglia and astrocytes, in order to determine those genes differentially expressed in the vulnerable cell population – i.e. motor neuron. The aim of the present study is to combine LCM and microarray analysis to determine those genes and pathways differentially expressed in MNs from human SOD1-related MND and to establish potential pathways for therapeutic intervention. Keywords: Human motor neurons The aim of this study was to determine the gene expression profiles from a small subset of cases which all carry mutations in the SOD1 gene. Expression profiles from isolated motor neurons in SOD1-related ALS cases were compared to those from control motor neurons, in order to establish the pathways implicated in SOD1-related motor neuronal cell death. The 'control' samples were originally submitted to GEO as GSE19332.
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2011-06-01 | E-GEOD-29652 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
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