Ontology highlight
ABSTRACT:
PROVIDER: PRJNA517482 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21613906_1.fastq.gz | Fastqsanger.gz | |||
| SRR21613906_2.fastq.gz | Fastqsanger.gz | |||
| SRR21613746_1.fastq.gz | Fastqsanger.gz | |||
| SRR21613746_2.fastq.gz | Fastqsanger.gz | |||
| SRR8497671_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 11 |
Similar Datasets
Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of early childhood with a poor survival rate thus there is a requirement for improved treatment strategies. Induced pluripotent stem cells offer the ability to model disease and develop new treatment strategies. JMML is frequently associated with mutations in PTPN11. Children with Noonan syndrome, a development disorder, have an increased incidence of JMML associated with specific germline mutations in PTPN11. We undertook a proteomic assessment of myeloid cells derived from induced pluripotent stem cells obtained from Noonan syndrome patients with PTPN11 mutations, either associated or not associated with increased incidence of JMML. We report that the proteomic perturbations induced by the leukaemia-associated PTPN11 mutations are associated with TP53 and NF-ĸb signalling. We have previously shown that MYC is involved in the differential gene expression observed in Noonan syndrome patients associated with increased incidence of JMML. Thus, we employed drugs to target these pathways and demonstrate differentential effects on clonogenic hematopoietic cells derived from Noonan syndrome patients whom develop JMML and those who do not. Further, we demonstrated these small molecular inhibitors, JQ1 and CBL0137, preferentially extinguish primitive haematopoietic cells from sporadic JMML patients as opposed to cells from healthy individuals.
2019-10-30 | PXD014708 | Pride
Project description:The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving tumor necrosis factor receptor (TNFR) superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling which markedly decreases the pro-apoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyl-transferase inhibitors (FTIs) should be examined in human autoimmune and lymphocyte homeostasis disorders. Experiment Overall Design: Describes the discovery of a new gene underlying a novel type of autoimmune lymphoproliferative syndrome, and characterizes the mechanisms involved in the pathogenesis of the disease.
2008-04-04 | E-GEOD-7345 | biostudies-arrayexpress
Project description:• Activating mutations of Shp2 cause conditions such as Noonan syndrome and juvenile myelomonocytic leukemia (JMML), with unmet therapeutic needs. • SFX-01, a sulforaphane complex, modifies cysteine residues and targets proteins including Shp2, where it induces an inhibitory modification at the active site of this protein phosphatase. • In a transgenic mouse model of Noonan syndrome and human JMML stem cells, SFX-01 normalized Shp2 activity, reduced myeloid cell counts, and induced cell-cycle arrest, highlighting its therapeutic potential.
2025-06-12 | PXD061655 | Pride
Project description:The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4-, CD8- ab T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving tumor necrosis factor receptor (TNFR) superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling which markedly decreases the pro-apoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyl-transferase inhibitors (FTIs) should be examined in human autoimmune and lymphocyte homeostasis disorders. Keywords: NRAS
2008-03-21 | GSE7345 | GEO
Project description:The protein tyrosine phosphatase SHP2, encoded by PTPN11, is an important regulator of Ras/MAPK signaling and a signaling hub downstream of receptor tyrosine kinases and other transmembrane receptors. Germline missense PTPN11 mutations cause developmental disorders such as Noonan Syndrome, whereas somatic mutations drive diverse cancers. While many pathogenic mutations enhance SHP2 catalytic activity, some are inactivating or alter protein-protein interactions, confounding our understanding of how SHP2 dysregulation causes diseases. Here, we perform multiplexed single-cell transcriptional profiling in cells expressing clinically diverse SHP2 variants, with and without receptor tyrosine kinase stimulation. We find that loss of catalytic activity does not phenocopy SHP2 knock-out at the gene expression level, and we show evidence for both convergent phenotypic effects from mechanistically distinct mutations, as well as the divergent effects from structurally similar mutations. These findings provide a framework for understanding how structural perturbations to SHP2 impact cellular outcomes.
2025-07-02 | GSE300865 | GEO
Project description:Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. Using unbiased proteomics, the protein targets of SFX-01, an α-cyclodextrin-stabilized isothiocyanate complex that covalently adducts cysteines that is in clinical development, were identified and included Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalised their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.
2025-06-13 | PXD061882 | Pride
Project description:SMAD4-associated Myhre syndrome mutations are under positive selection in the male germline
| PRJEB64495 | ENA
Project description:Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality early in life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, by analysis of sarcomeric myosin conformational states, histopathology and gene expression in left ventricular myocardial tissue from NS-CM, HCM and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.
2022-01-11 | GSE188238 | GEO
Project description:Leucine-zipper-like transcriptional regulator 1 (LZTR1) is a member of the BTB-Kelch superfamily, which regulates the RAS proteostasis. Autosomal dominant (AD) mutations in LZTR1 have been identified in patients with Noonan syndrome (NS), a congenital anomaly syndrome. However, it remains unclear whether LZTR1 regulates the proteostasis of the RAS subfamily molecules and activate MAPK signaling pathway in heart. To investigate the impact of the LZTR1 mutant on gene expression, we performed RNA-seq analyses using LVs.
2024-10-23 | GSE254067 | GEO
Project description:We profiled RNA expression in human iPSC-derived cardiomyocytes from patients with LZTR1-associated Noonan syndrome
2020-12-01 | GSE145349 | GEO