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SRP041831
Homo sapiens
5 Downloadable Samples
IlluminaHiSeq2000
Description
The aim of this study is to identify the SPIN1 target genes in liposarcoma cells Overall design: Liposarcoma is one of the most common histological subtypes of soft tissue sarcoma and causes high incidence of morbidity and mortality. Since therapeutic options for liposarcoma treatment are insufficient, there is an urgent need to identify novel therapeutic targets. Here, we show that knockdown of SPIN1, a reader of H3K4me3 and H3R8me2a chromatin marks, strongly reduces proliferation and survival of liposarcoma cells in vitro and in xenograft mouse models. Combining genome-wide chromatin binding and transcriptome analyses, we found that SPIN1 in cooperation with the transcription factor MAZ directly enhances expression of GDNF, an activator of the RET signaling pathway. Accordingly, knockdown of SPIN1 results in reduced levels of GDNF and activated RET explaining diminished liposarcoma cell proliferation and survival. In line with these observations, levels of SPIN1, GDNF, and activated RET are highly increased in human liposarcoma compared to lipoma or normal adipose tissue. Importantly, SPIN1-mediated transcriptional control depends on binding to H3K4me3 suggesting that targeting of this interaction with small molecule inhibitors is a novel strategy to treat liposarcoma.
Publication Title
The histone code reader SPIN1 controls RET signaling in liposarcoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 18 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Stem cells reside in specific niches providing stemness-maintaining environments. Thus, the regulated migration from these niches is associated with differentiation onset. However, mechanisms retaining stem cells in their niche remain poorly understood. Here, we show that the epigenetic regulator lysine-specific demethylase 1 (Lsd1) organises the trophoblast niche of the early mouse embryo by coordinating migration and invasion of trophoblast stem cells (TSCs). Lsd1 deficiency leads to the depletion of the stem cell pool resulting from precocious migration of TSCs.
Publication Title
Lysine-specific demethylase 1 regulates differentiation onset and migration of trophoblast stem cells.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina MouseWG-6 v2.0 R2 expression beadchip
Description
Examination of gene expression patterns in lineage negative FLT3-ITD and pMIG-transduced BM cells via microarray study.
Publication Title
RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Clariom S Human array (clariomshuman)
Description
Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.
Publication Title
Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.
Sample Metadata Fields
Specimen part, Treatment, Time
View Samples