Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome
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ABSTRACT:
PROVIDER: PRJNA705198 | ENA |
REPOSITORIES: ENA
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Project description:Hematopoietic stem and progenitor cells derived from a zebrafish model of Noonan syndrome, carrying a patient-associated Shp2-D61G mutation, display an expansion of monocyte/macrophage progenitors with an inflammatory gene expression signature.
2021-02-27 | GSE167787 | GEO
Project description:Noonan syndrome (NS) is a genetic disorder mainly caused by gain-of-function mutations of SHP2. Although diverse neurological manifestations are commonly diagnosed in NS patients, mechanisms on how the SHP2 mutation induces the neurodevelopmental defects remain elusive. Here, we report that cortical organoids (NS-COs) derived from NS-induced pluripotent stem cells (iPSCs) exhibit developmental abnormalities, especially in excitatory neurons (ENs). Although NS-COs normally develop in appearance, single-cell transcriptomic analysis represented increment of EN population and overexpression of cortical layer markers in NS-COs. Surprisingly, EN subpopulation co-expressing upper layer marker SATB2 and deep layer maker CTIP2 was enriched in NS-COs during the cortical development. In parallel with the developmental disruptions, NS-COs also exhibited reduced synaptic connectivity. Collectively, our findings suggest that perturbed cortical layer identity and impeded neuronal connectivity account for the neurological manifestations of NS.
2023-04-24 | GSE213798 | GEO
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: Not available
| S-EPMC2151089 | biostudies-literature
Project description:Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome
| PRJNA777959 | ENA
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:Activating mutations in PTPN11 gene are the most frequent in JMML patients. Here we explore the transcriptome of HSPC (hematopoietic stem and progenitor cells) sorted from sporadic JMML patients with PTPN11 mutation and from healthy age matched donnors. Bulk transcriptome of sorted HSPC reveals an inflammatory gene expression signature which may represent a future target for JMML therapy.
2021-09-06 | GSE183252 | GEO
Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia hat only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HSPC (hematopoietic stem and progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HSPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples. Methylation profile on bulk mononucleated cell on theses JMML patients, 2 healthy postnatal and 2 healthy prenatal samples is also investigated. The results show a global hypermethylation in JMML samples compared to healthy samples and a specific JMML group with a hypermethylated profile compared to all JMML samples.
2022-12-31 | GSE198919 | GEO
Project description:JMML (Juvenile myelomonocytic leukaemia) is a leukaemia that only develops in young children and is thought to have a prenatal initiation. To study the relationship between JMML and normal ontogeny we studied the transcriptome of HPC (hematopoietic progenitor cells) sorted from sporadic JMML patients, healthy prenatal samples and from healthy age matched donors. Bulk transcriptome of sorted HPC reveals that some JMML samples cluster with prenatal samples whereas other from a distinct cluster apart from any healthy samples.
2024-05-16 | GSE267628 | GEO
Project description:1205Lu Metastatic Human melanoma cell lines with knockdown of Shp2 (PTPN11) were grown as xenograft tumors in NSG mice. RNA was extracted from the tumors and analyzed on [HuGene-2_0-st] Affymetrix Human Gene 2.0 ST Array [transcript (gene) version] Shp2 knockdown compared with non-target controls
2016-07-03 | E-GEOD-53282 | biostudies-arrayexpress