Spindle cell lesions with oncogenic EGFR kinase domain aberrations: expanding the spectrum of protein kinase-related mesenchymal tumors
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PROVIDER: PRJNA1089615 | ENA |
REPOSITORIES: ENA
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Project description:EGFR aberrations are reported in a subset of myofibroblastic lesions with kinase domain duplication (EGFR-KDD) and exon 20 mutations being assigned to infantile fibrosarcomas (IFS), mesoblastic nephroma and fibrous hamartoma of infancy (FHI), respectively. In this retrospective study, we correlated molecular findings with histomorphology of 14 myofibroblastic lesions harboring such genetic changes identified by NGS. We additionally performed DNA methylation profiling (DNAmp) and immunohistochemistry. Lesions were from 10 males and 4 females with a mean age of 3 years (range, 0.3 -14) and occurred subcutaneously in the upper limbs (n = 5), lower limbs (n = 3), back/thorax (n = 5), and the nasal cavity (n = 1). Eleven were cured by surgery, including one relapsed case. Two patients were lost to follow-up. One case was very recent, and the patient was biopsied. Histologically, the lesions showed a wide spectrum varying from classic FHI (n=9) to IFS (n=1) or lipofibromatosis-like tumors (LFT) (n=2) or dermatofibrosarcoma protuberans-like (DFSP) (n=1) to a predominantly-myxoid spindle cell lesion (n=1). Immunohistochemically, all neoplasms stained with CD34, while S100 was positive in 2/14. EGFR expression was observed in 9/10 cases. Molecularly, the IFS and one LFT harbored EGFR-KDD, while an exon 20 mutation was identified in all FHI, one LFT and in the DFSP and predominantly myxoid spindle cell lesion. By DNAmp, all but two cases formed a well-defined cluster, demonstrating that these lesions are also epigenetically related. In conclusion, EGFR kinase domain aberrations found in FHI, IFS, LFN, DFSP and a spindle cell lesion with a predominant myxoid stroma of children and adolescents show that these neoplasms with a broad morphological spectrum belong to the group of protein kinase-related lesions with a distinct epigenetic signature. Molecular analyses, including DNAmp, help to identify and characterize this emerging category and become mandatory when targeted treatment is considered.
2024-06-17 | GSE261945 | GEO
Project description:The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well-established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis. Here we demonstrate that CK1α, of the casein kinase 1 family of protein kinases, localises to the spindle and is required for proper spindle-positioning and timely cell division. CK1α is recruited to the spindle by FAM83D, and cells devoid of FAM83D, or those harbouring CK1α-binding-deficient FAM83DF283A/F283A knockin mutation, display pronounced spindle-positioning defects, and a prolonged mitosis. Restoring FAM83D at the endogenous locus in FAM83D-/- cells, or artificially delivering CK1α to the spindle in FAM83DF283A/F283A cells, rescues these defects. These findings implicate CK1α as new mitotic kinase that orchestrates the kinetics and orientation of cell division.
2019-07-15 | PXD013808 | Pride
Project description:Inherited mitochondrial DNA (mtDNA) diseases transmit maternally and cause severe phenotypes. Since no effective treatment or genetic screening is available, nuclear genome transfer between patients’ and healthy eggs to replace mutant mtDNAs holds promises. Since polar body contains very few mitochondria and share same genomic material as oocyte, here we perform polar body transfer to prevent the transmission of inherited mtDNA variants. We compare the value of different germline genome transfer (spindle-chromosome, pronuclear, first and second polar body) in a mouse model. Reconstructed embryos support normal fertilization and produce live offspring. Strikingly, genetic analysis confirms F1 generation after polar body transfer possesses minimal donor mtDNA carry-over compared with spindle-chromosome (low/medium carry-over) and pronuclear (medium/high carry-over) transfer. Moreover, mtDNA genotype remains stable in F2 generation of progeny after polar body transfer. Our preclinical model demonstrates polar body transfer holds great potential in preventing the transmission of inherited mtDNA diseases. The objective of the present study was to detect genomic aberrations between PB1 and its counterpart, spindle-chromosome complex in human MII oocyte, PB2 and female pronucleus in human zygote at a single-cell level.
2014-06-19 | E-GEOD-56676 | biostudies-arrayexpress
Project description:The spindle checkpoint is a mitotic surveillance system which ensures equal segregation of sister chromatids. It delays anaphase onset by inhibiting the action of the E3 ubiquitin ligase known as the anaphase promoting complex or cyclosome (APC/C). Mads/BubR1 is a key component of the mitotic checkpoint complex (MCC) which binds and inhibits the APC/C early in mitosis. Mps1Mph1 kinase is critical for checkpoint signalling and MCC-APC/C inhibition, yet few substrates have been identified. Here we identify Mad3 as a substrate of fission yeast Mps1Mph1 kinase. We map and mutate phosphorylation sites in Mad3, producing mutants that are targeted to kinetochores and assembled into MCC, yet display reduced APC/C binding and are unable to maintain checkpoint arrests. We chow biochemically that Mad3 phospho-mimics are potent APC/C inhibitors in vitro, demonstrating that Mad3p modification can directly influence Cdc20Slp1-APC/C activity. This genetic dissection of APC/C inhibition demonstrates that Mps1Mph1 kinase-dependant modification of Mad3 and Mad2 act in a concerted manner to maintain spindle checkpoint arrests.
2016-03-31 | PXD003806 | Pride
Project description:The transition from meiotic divisions in the oocyte to mitotic divisions in the early embryo is a critical step in animal development. Despite negligible changes to cell size, shape, and content, following fertilization the small, barrel-shaped meiotic spindle is replaced by a large zygotic spindle that nucleates abundant astral microtubules at spindle poles. To identify underlying mechanisms, we applied a drug screening approach using eggs of the simple chordate Ciona robusta (sea squirt) and found that inhibition of Casein Kinase 2 (CK2) caused a shift from meiotic to mitotic-like spindle morphology with nucleation of robust astral microtubule arrays, an effect reproduced in Xenopus laevis (frog) egg extracts. In both species, a kinase assay revealed that CK2 activity decreases at fertilization. To identify substrates and downstream effectors, we assessed the global phosphoproteomic changes that accompany both the meiosis to mitosis transition and CK2 inhibition in Xenopus, which identified components of the Ran-GTP pathway as potential downstream targets. Inhibition of Ran-GTP-driven microtubule nucleation suppressed CK2-induced spindle morphology changes in both Xenopus and Ciona. These data support a model in which attenuation of CK2 activity at fertilization in chordates leads to activation of Ran-regulated spindle assembly factors that drive microtubule growth and the transition to mitotic spindle morphology.
2024-07-04 | MSV000095250 | MassIVE
Project description:This case shows similarities with 2 previously reported cases, including intraventricular location, histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and immunophenotype with co-expression of OLIG2, GFAP and synaptophysin. The onset in an infant, the presence of a high-grade component and the leptomeningeal dissemination, however, have not been previously reported in EWSR1-PATZ1 rearranged tumors, expanding the clinico-pathological spectrum.
2020-12-03 | GSE162537 | GEO
Project description:A series of conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were generated and validated for relavence to corresponding human cancers. Conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were created by activation or deletion of Pax3:Fkhr, p53, Ptch1 or Rb1 genes.
2011-02-17 | E-GEOD-22520 | biostudies-arrayexpress
Project description:The oocytes of many species, both invertebrate and vertebrate, contain a large collection of localized determinants in the form of proteins and translationally inactive maternal mRNAs. However, it is unknown whether mouse oocytes contain localized MmRNA determinants and what mechanisms might be responsible for their control. We collected intact MII oocytes, enucleated MII oocyte cytoplasts (with the spindle removed), and spindle-chromosome complexes which had been microsurgically removed. RNA was extracted, amplified, labeled, and applied to microarrays to determine if any MmRNA determinants were localized to the SCC. We used microarrays to determine whether maternal mRNAs in mouse oocytes are enriched in the meiotic spindle
2013-11-06 | E-GEOD-46875 | biostudies-arrayexpress
Project description:Methanosarcina spindle-shaped virus 1 Metagenomic assembly
| PRJNA1132277 | ENA
Project description:Potato spindle tuber viroid strain:intermediate
| PRJNA1031346 | ENA