- MeSH
- chronická lymfatická leukemie metabolismus mortalita patologie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikro RNA biosyntéza MeSH
- míra přežití MeSH
- následné studie MeSH
- přežití bez známek nemoci MeSH
- RNA nádorová biosyntéza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
The information on candidate cancer driver alterations available from public databases is often descriptive and of limited mechanistic insight, which poses difficulties for reliable distinction between true driver and passenger events. To address this challenge, we performed in-depth analysis of whole-exome sequencing data from cell lines generated by a barrier bypass-clonal expansion (BBCE) protocol. The employed strategy is based on carcinogen-driven immortalization of primary mouse embryonic fibroblasts and recapitulates early steps of cell transformation. Among the mutated genes were almost 200 COSMIC Cancer Gene Census genes, many of which were recurrently affected in the set of 25 immortalized cell lines. The alterations affected pathways regulating DNA damage response and repair, transcription and chromatin structure, cell cycle and cell death, as well as developmental pathways. The functional impact of the mutations was strongly supported by the manifestation of several known cancer hotspot mutations among the identified alterations. We identified a new set of genes encoding subunits of the BAF chromatin remodeling complex that exhibited Ras-mediated dependence on PRC2 histone methyltransferase activity, a finding that is similar to what has been observed for other BAF subunits in cancer cells. Among the affected BAF complex subunits, we determined Smarcd2 and Smarcc1 as putative driver candidates not yet fully identified by large-scale cancer genome sequencing projects. In addition, Ep400 displayed characteristics of a driver gene in that it showed a mutually exclusive mutation pattern when compared with mutations in the Trrap subunit of the TIP60 complex, both in the cell line panel and in a human tumor data set. We propose that the information generated by deep sequencing of the BBCE cell lines coupled with phenotypic analysis of the mutant cells can yield mechanistic insights into driver events relevant to human cancer development.
- MeSH
- exom genetika MeSH
- fibroblasty MeSH
- lidé MeSH
- mutace MeSH
- myši MeSH
- nádorová transformace buněk genetika MeSH
- nádorové proteiny genetika MeSH
- nádory genetika MeSH
- primární buněčná kultura MeSH
- vysoce účinné nukleotidové sekvenování * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
PU.1 downregulation within hematopoietic stem and progenitor cells (HSPCs) is the primary mechanism for the development of acute myeloid leukemia (AML) in mice with homozygous deletion of the upstream regulatory element (URE) of PU.1 gene. p53 is a well-known tumor suppressor that is often mutated in human hematologic malignancies including AML and adds to their aggressiveness; however, its genetic deletion does not cause AML in mouse. Deletion of p53 in the PU.1(ure/ure) mice (PU.1(ure/ure)p53(-/-)) results in more aggressive AML with shortened overall survival. PU.1(ure/ure)p53(-/-) progenitors express significantly lower PU.1 levels. In addition to URE deletion we searched for other mechanisms that in the absence of p53 contribute to decreased PU.1 levels in PU.1(ure/ure)p53(-/-) mice. We found involvement of Myb and miR-155 in downregulation of PU.1 in aggressive murine AML. Upon inhibition of either Myb or miR-155 in vitro the AML progenitors restore PU.1 levels and lose leukemic cell growth similarly to PU.1 rescue. The MYB/miR-155/PU.1 axis is a target of p53 and is activated early after p53 loss as indicated by transient p53 knockdown. Furthermore, deregulation of both MYB and miR-155 coupled with PU.1 downregulation was observed in human AML, suggesting that MYB/miR-155/PU.1 mechanism may be involved in the pathogenesis of AML and its aggressiveness characterized by p53 mutation.
- MeSH
- aktivace transkripce MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- játra patologie MeSH
- lidé MeSH
- mikro RNA genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši knockoutované MeSH
- myši MeSH
- nádorový supresorový protein p53 genetika MeSH
- onkogenní proteiny v-myb genetika metabolismus MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní proteiny c-myc genetika metabolismus MeSH
- protoonkogenní proteiny genetika MeSH
- regulace genové exprese u leukemie MeSH
- slezina patologie MeSH
- trans-aktivátory genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Hematopoiesis is coordinated by a complex regulatory network of transcription factors and among them PU.1 (Spi1, Sfpi1) represents a key molecule. This review summarizes the indispensable requirement of PU.1 during hematopoietic cell fate decisions and how the function of PU.1 can be modulated by protein-protein interactions with additional factors. The mutual negative regulation between PU.1 and GATA-1 is detailed within the context of normal and leukemogenic hematopoiesis and the concept of 'differentiation therapy' to restore normal cellular differentiation of leukemic cells is discussed.
- MeSH
- hematopoéza fyziologie MeSH
- leukemie metabolismus patologie MeSH
- lidé MeSH
- protoonkogenní proteiny fyziologie MeSH
- trans-aktivátory fyziologie MeSH
- transkripční faktory GATA fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- MeSH
- apoptóza účinky záření MeSH
- inhibitory růstu farmakologie MeSH
- membránové glykoproteiny farmakologie chemie MeSH
- myelodysplastické syndromy patologie MeSH
- myeloidní leukemie patologie MeSH
- myši MeSH
- nádorové kmenové buňky účinky léků MeSH
- tumor nekrotizující faktory farmakologie genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- Fanconiho anemie genetika MeSH
- lidé MeSH
- pseudogeny MeSH
- ribozomální proteiny genetika MeSH
- Check Tag
- lidé MeSH
