Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN). However, the mechanism by which mutant CALR is oncogenic is unknown. Here, we demonstrate that a megakaryocytic-specific MPN phenotype is induced when mutant CALR is over-expressed in mice and that the thrombopoietin receptor, MPL is required for mutant CALR driven transformation. Whole transcriptome analysis reveals enrichment of STAT signatures in mutant CALR transformed cells and JAK2 inhibitor treatment abrogates STAT activation. Employing extensive mutagenesis-based structure-function analysis we demonstrate that the positively charged amino acids within the mutant CALR C-terminus are required for cellular transformation through facilitating physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel mechanism of cancer pathogenesis. Overall design: Transcriptomes derived from BA/F3-MPL cells transformed with human wild-type CALR, human mutant CALR 52bp del, or Empty vector, at time zero (t0) and 24 hours (t24) after IL3-withdrawal culture were generated by deep sequencing, two replicas, by HiSeq2000.
Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.
Cell line, Subject
View SamplesCell-cell communication is critical for stem cell maintenance. Shoot apical meristem (SAM) located at the shoot tip harbors stem cells within the central zone (CZ). Their progeny differentiate in the adjacent peripheral zone (PZ). WUSCHEL (WUS) is a homeodomain transcription factor produced in a few cells of the organizing center (OC), located beneath the CZ. It has been shown to specify stem cell fate and also activate CLAVATA3 (CLV3) expression in cells of the CZ. CLV3 is a secreted peptide that activates a membrane bound receptor kinase-CLAVATA1 to restrict WUS transcription to the OC. It has been hypothesized that WUS activates CLV3 expression and stem cell fate in adjacent cells of the CZ by activating a non-cell autonomous signal. Contrary to this hypothesis, here we show that the WUS protein after being synthesized in cells of the OC, migrates into the superficial cell layers of the CZ where it activates CLV3 transcription by binding to its promoter elements. WUS also migrates laterally into the PZ to repress the expression of differentiation promoting transcription factors by binding to their regulatory regions. Migration of a stem cell inducing transcription factor into adjacent cells to activate a negative regulator, whereby restricting its own accumulation is unique to plant stem cell niches. While stem cell promoting transcription factor directly repressing differentiation promoting transcription factors to prevent premature differentiation of stem cell progenitors is conserved among diverse stem cell niches.
Plant stem cell maintenance involves direct transcriptional repression of differentiation program.
Treatment
View SamplesDifferential gene expression assessed in siTNF-OMe-P treated animals showed significant correlation between improved colon integrity and clinical parameters of colitis with reduced TLR activation, tissue regeneration and reduced pro-inflammatory cytokines, as compared to all treatment groups.
Functionally enhanced siRNA targeting TNFα attenuates DSS-induced colitis and TLR-mediated immunostimulation in mice.
Specimen part, Treatment
View SamplesGEP of the murine cell line BAL17 (BALB/c)
Mechanisms of intracerebral lymphoma growth delineated in a syngeneic mouse model of central nervous system lymphoma.
Specimen part
View SamplesID8-based ovarian tumors were developed for 3 weeks in wild type (WT, N=3) or conditional knockout mice selectively deleting XBP1 in CD11c positive cells (KO, N=3). Tumor-associated DCs were independently sorted via FACS and used for transcriptional profiling. Overall design: Total RNA from sorted tumor-associated DCs (N=3/genotype) was independently isolated using the miRVANA kit (Life Technologies) and further purified and concentrated using minElute columns (Qiagen). RNA integrity was confirmed using an Agilent Bioanalyzer 2100.
ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis.
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View SamplesThis SuperSeries is composed of the SubSeries listed below.
Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
Sex, Age, Specimen part
View SamplesIn preeclampsia (PE), cytotrophoblast (CTB) invasion of the uterus and spiral arteries is often shallow. Thus, the placentas role has been a focus. We hypothesized that decidual defects are an important determinant of the placental phenotype. We isolated (human) endometrial stromal cells (hESCs) from non-pregnant donors with a prior pregnancy that was complicated by severe PE (sPE). Versus controls, they failed to decidualize as demonstrated by morphological criteria and the analysis of stage-specific antigens. These results were bolstered by showing that they were transcriptionally inert. Additionally, we used laser microdissection to isolate the decidua from tissue sections of the maternal-fetal interface. Transcriptional profiling revealed sPE-associated defects in gene expression. Also, decidual cells from sPE patients, which de-differentiated in vitro, failed to re-decidualize in culture. Immediately following isolation they released factors that inhibited CTB invasion, linking a possible cause to a known effect. These data suggested that failed decidualization is an important contributor to down regulated CTB invasion in sPE. Diagnosis of this defect prior to pregnancy would enable therapies that are designed to improve decidualization, a novel strategy for prevention.
Defective decidualization during and after severe preeclampsia reveals a possible maternal contribution to the etiology.
Specimen part
View SamplesThe presence of some malignancies, such as cancer, impacts on peripheral blood mononuclear cells (PBMCs) gene expression profiling, suggesting the potential suitability of these genes as diagnostic and prognostic markers.
Transcriptional profiling of peripheral blood in pancreatic adenocarcinoma patients identifies diagnostic biomarkers.
Sex, Age, Specimen part, Disease, Disease stage
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells.
Specimen part, Cell line
View SamplesThis SuperSeries is composed of the SubSeries listed below.
The Activation-Induced Assembly of an RNA/Protein Interactome Centered on the Splicing Factor U2AF2 Regulates Gene Expression in Human CD4 T Cells.
Specimen part
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