Akútna myeloidná leukémia (AML) je značne heterogénny podtyp leukémie, ktorý predstavuje 25 % všetkých detských leukémií. Prítomnosťou genetických mutácií v kmeňových krvotvorných/progenitorových bunkách produkuje kostná dreň veľké množstvo abnormálnych nediferencovaných leukocytov (blastov), čo výrazne narúša správnu diferenciáciu buniek. AML je indukovaná dvomi zásahmi. Chromozomálna translokácia počas hematopoézy vnútromaternicového vývoja predstavuje prvý zásah. Tak vzniknú preleukemické fúzne gény (PFG), ktoré sa môžu neskôr transformovať druhým zásahom (bodová genetická mutácia - delécia, inzercia...) na funkčný malígny klon. Medzi charakteristické fúzne gény AML patria napríklad AML1-ETO, PML‐RARA či MLL‐AF9, ktoré následne produkujú hybridné proteíny so zmenenou funkciou. Viaceré štúdie poukazujú na to, že tieto PFG sú považované za dôležitý prognostický nástroj pri hodnotení ochorení. Zatiaľ čo výskyt PFG charakteristických pre akútnu lymfoblastickú leukémiu (ALL) je relatívne dobre preskúmaný a odhadoval sa na 1 až 5 % v pupočníkovej krvi zdravých novorodencov, PFG relevantné pre AML stále nie sú dostatočne objasnené.
Acute myeloid leukemia (AML) is a highly heterogeneous subtype of leukemia, accounting for 25 % of childhood leukemias. By the presence of genetic mutations in hematopoietic/ progenitor stem cells, the bone marrow produces a large number of abnormal undifferentiated leukocytes (blasts), which significantly impairs the proper differentiation of cells. AML is induced by two interventions. Chromosomal translocation during hematopoiesis of intrauterine development is the first intervention. This creates preleukemic fusion genes (PFG), which can later be transformed by a second intervention (point genetic mutation - deletion, insertion ...) into a functional malignant clone. Characteristic AML fusion genes include AML1-ETO, PML-RARA or MLL-AF9, which in turn produce hybrid proteins with altered function. Several studies suggest that these PFGs are considered an important prognostic tool in disease assessment. While the incidence of PFG characteristic of acute lymphoblastic leukemia (ALL) has been relatively well studied by several research groups and has been estimated at 1 to 5% in the umbilical cord blood of healthy neonates, PFG relevant to AML are still not sufficiently clarified.
- MeSH
- akutní myeloidní leukemie * diagnóza genetika MeSH
- alfa receptor kyseliny retinové genetika MeSH
- fúzní onkogenní proteiny * genetika MeSH
- lidé MeSH
- protein PEBP2A2 genetika MeSH
- protein promyelocytické leukemie genetika MeSH
- protoonkogenní protein MLL genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Diverse stress insults trigger interactions of PML with nucleolus, however, the function of these PML nucleolar associations (PNAs) remains unclear. Here we show that during induction of DNA damage-induced senescence in human non-cancerous cells, PML accumulates at the nucleolar periphery simultaneously with inactivation of RNA polymerase I (RNAP I) and nucleolar segregation. Using time-lapse and high-resolution microscopy, we followed the genesis, structural transitions and destiny of PNAs to show that: 1) the dynamic structural changes of the PML-nucleolar interaction are tightly associated with inactivation and reactivation of RNAP I-mediated transcription, respectively; 2) the PML-nucleolar compartment develops sequentially under stress and, upon stress termination, it culminates in either of two fates: disappearance or persistence; 3) all PNAs stages can associate with DNA damage markers; 4) the persistent, commonly long-lasting PML multi-protein nucleolar structures (PML-NDS) associate with markers of DNA damage, indicating a role of PNAs in persistent DNA damage response characteristic for senescent cells. Given the emerging evidence implicating PML in homologous recombination-directed DNA repair, we propose that PNAs contribute to sequestration and faithful repair of the highly unstable ribosomal DNA repeats, a fundamental process to maintain a precise balance between DNA repair mechanisms, with implications for genomic integrity and aging.
- MeSH
- buněčné jadérko metabolismus MeSH
- doxorubicin MeSH
- fyziologický stres MeSH
- kultivované buňky MeSH
- lidé MeSH
- poškození DNA * MeSH
- protein promyelocytické leukemie metabolismus MeSH
- stárnutí buněk * MeSH
- zobrazování trojrozměrné MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The bulk of DNA damage caused by ionizing radiation (IR) is generally repaired within hours, yet a subset of DNA lesions may persist even for long periods of time. Such persisting IR-induced foci (pIRIF) co-associate with PML nuclear bodies (PML-NBs) and are among the characteristics of cellular senescence. Here we addressed some fundamental questions concerning the nature and determinants of this co-association, the role of PML-NBs at such sites, and the reason for the persistence of DNA damage in human primary cells. We show that the persistent DNA lesions are devoid of homologous recombination (HR) proteins BRCA1 and Rad51. Our super-resolution microscopy-based analysis showed that PML-NBs are juxtaposed to and partially overlap with the pIRIFs. Notably, depletion of 53BP1 resulted in decreased intersection between PML-NBs and pIRIFs implicating the RNF168-53BP1 pathway in their interaction. To test whether the formation and persistence of IRIFs is PML-dependent and to investigate the role of PML in the context of DNA repair and senescence, we genetically deleted PML in human hTERT-RPE-1 cells. Unexpectedly, upon high-dose IR treatment, cells displayed similar DNA damage signalling, repair dynamics and kinetics of cellular senescence regardless of the presence or absence of PML. In contrast, the PML knock-out cells showed increased sensitivity to low doses of IR and DNA-damaging agents mitomycin C, cisplatin and camptothecin that all cause DNA lesions requiring repair by HR. These results, along with enhanced sensitivity of the PML knock-out cells to DNA-PK and PARP inhibitors implicate PML as a factor contributing to HR-mediated DNA repair.
- MeSH
- 53BP1 metabolismus MeSH
- genový knockout MeSH
- intranukleární inkluzní tělíska metabolismus účinky záření MeSH
- lidé MeSH
- oprava DNA * účinky záření MeSH
- poškození DNA * MeSH
- protein promyelocytické leukemie nedostatek genetika metabolismus MeSH
- stárnutí buněk genetika účinky záření MeSH
- ubikvitinligasy metabolismus MeSH
- vztah dávky záření a odpovědi MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
