- Publikační typ
- abstrakt z konference MeSH
Myeloproliferative neoplasms (MPN) are genetically very complex and heterogeneous diseases in which the acquisition of a somatic driver mutation triggers three main myeloid cytokine receptors, and phenotypically expresses as polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The course of the diseases may be influenced by germline predispositions, modifying mutations, their order of acquisition and environmental factors such as aging and inflammation. Deciphering these contributory elements, their mutual interrelationships, and their contribution to MPN pathogenesis brings important insights into the diseases. Animal models (mainly mouse and zebrafish) have already significantly contributed to understanding the role of several acquired and germline mutations in MPN oncogenic signaling. Novel technologies such as induced pluripotent stem cells (iPSCs) and precise genome editing (using CRISPR/Cas9) contribute to the emerging understanding of MPN pathogenesis and clonal architecture, and form a convenient platform for evaluating drug efficacy. In this overview, the genetic landscape of MPN is briefly described, with an attempt to cover the main discoveries of the last 15 years. Mouse and zebrafish models of the driver mutations are discussed and followed by a review of recent progress in modeling MPN with patient-derived iPSCs and CRISPR/Cas9 gene editing.
- MeSH
- dánio pruhované MeSH
- esenciální trombocytemie genetika MeSH
- fenotyp MeSH
- indukované pluripotentní kmenové buňky metabolismus MeSH
- Janus kinasa 2 genetika MeSH
- kalretikulin genetika MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mutace MeSH
- myeloproliferativní poruchy genetika patofyziologie MeSH
- myši MeSH
- nádory genetika MeSH
- polycythaemia vera genetika MeSH
- primární myelofibróza genetika MeSH
- receptory thrombopoetinu genetika MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The patients with mantle cell lymphoma (MCL) have translocation t(11;14) associated with cyclin D1 overexpression. We observed that iron (an essential cofactor of dioxygenases including prolyl hydroxylases [PHDs]) depletion by deferoxamine blocked MCL cells' proliferation, increased expression of DNA damage marker γH2AX, induced cell cycle arrest and decreased cyclin D1 level. Treatment of MCL cell lines with dimethyloxalylglycine, which blocks dioxygenases involving PHDs by competing with their substrate 2-oxoglutarate, leads to their decreased proliferation and the decrease of cyclin D1 level. We then postulated that loss of EGLN2/PHD1 in MCL cells may lead to down-regulation of cyclin D1 by blocking the degradation of FOXO3A, a cyclin D1 suppressor. However, the CRISPR/Cas9-based loss-of-function of EGLN2/PHD1 did not affect cyclin D1 expression and the loss of FOXO3A did not restore cyclin D1 levels after iron chelation. These data suggest that expression of cyclin D1 in MCL is not controlled by ENGL2/PHD1-FOXO3A pathway and that chelation- and 2-oxoglutarate competition-mediated down-regulation of cyclin D1 in MCL cells is driven by yet unknown mechanism involving iron- and 2-oxoglutarate-dependent dioxygenases other than PHD1. These data support further exploration of the use of iron chelation and 2-oxoglutarate-dependent dioxygenase inhibitors as a novel therapy of MCL.
- MeSH
- aminokyseliny dikarboxylové farmakologie MeSH
- chelátory železa farmakologie MeSH
- cyklin D1 metabolismus MeSH
- deferoxamin farmakologie MeSH
- dioxygenasy antagonisté a inhibitory metabolismus MeSH
- down regulace účinky léků MeSH
- hydroxylace MeSH
- hypoxie buňky účinky léků MeSH
- inhibitory enzymů farmakologie MeSH
- kyseliny ketoglutarové farmakologie MeSH
- lidé MeSH
- lymfom z plášťových buněk enzymologie MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- poškození DNA MeSH
- prolyl-4-hydroxylasy HIF metabolismus MeSH
- protein FOXO3 genetika metabolismus MeSH
- železo nedostatek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Erythropoietin (EPO) is recognized for neuroprotective and angiogenic effects and has been associated with aging and neovascular age-related macular degeneration (AMD). We hypothesized that systemic EPO facilitates the development of choroidal neovascularization (CNV). Wild type mice expressed murine EPOR (mWtEPOR) in RPE/choroids at baseline and had significantly increased serum EPO after laser treatment. To test the role of EPO signaling, we used human EPOR knock-in mice with the mWtEPOR gene replaced by either the human EPOR gene (hWtEPOR) or a mutated human EPOR gene (hMtEPOR) in a laser-induced choroidal neovascularization (LCNV) model. Loss-of-function hWtEPOR mice have reduced downstream activation, whereas gain-of-function hMtEPOR mice have increased EPOR signaling. Compared to littermate controls (mWtEPOR), hMtEPOR with increased EPOR signaling developed larger CNV lesions. At baseline, hMtEPOR mice had increased numbers of macrophages, greater expression of macrophage markers F4/80 and CD206, and following laser injury, had greater expression of cytokines CCL2, CXCL10, CCL22, IL-6, and IL-10 than mWtEPOR controls. These data support a hypothesis that injury from age- and AMD-related changes in the RPE/choroid leads to choroidal neovascularization through EPOR-mediated cytokine production.
- MeSH
- choroidea krevní zásobení metabolismus MeSH
- cytokiny metabolismus MeSH
- erythropoetin metabolismus MeSH
- kultivované buňky MeSH
- makrofágy cytologie fyziologie MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- neovaskularizace choroidey metabolismus patologie MeSH
- receptory erythropoetinu fyziologie MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
We describe the molecular etiology of β(+)-thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the β-globin gene (HBB). The transcript level of the affected β-globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed β-globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the β-globin(L1) allele also resulted from a reduced rate of transcription and decreased production of full-length β-globin primary transcripts. The promoter and enhancer sequences of the β-globin(L1) allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the β-globin(L1) transcription despite permanent β-globin(L1) promoter CpG methylation. This result indicates that the decreased rate of transcription from the β-globin(L1) allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the β-globin gene represents a novel etiology of β-thalassemia.
- MeSH
- alely MeSH
- alternativní sestřih MeSH
- beta-globiny genetika MeSH
- beta-talasemie genetika MeSH
- CpG ostrůvky MeSH
- dlouhé rozptýlené jaderné elementy * MeSH
- dospělí MeSH
- genetická transkripce MeSH
- introny * MeSH
- inzerční mutageneze * MeSH
- lidé MeSH
- metylace DNA MeSH
- pořadí genů MeSH
- promotorové oblasti (genetika) MeSH
- regulace genové exprese MeSH
- stabilita RNA MeSH
- umlčování genů MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- MeSH
- alely MeSH
- B-lymfocyty metabolismus MeSH
- buněčný rodokmen MeSH
- chronická lymfatická leukemie MeSH
- granulocyty metabolismus MeSH
- hematopoetické kmenové buňky * metabolismus patologie MeSH
- inaktivace chromozomu X MeSH
- Janus kinasa 2 * genetika metabolismus MeSH
- lidé MeSH
- mutace * MeSH
- nádorová transformace buněk * genetika metabolismus MeSH
- polycythaemia vera MeSH
- senioři MeSH
- substituce aminokyselin MeSH
- T-lymfocyty metabolismus MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
Tato práce pojednává o některých klíčových aspektech diagnostických kritérií pro MPN podle klasifikace Světové zdravotnické organizace (WHO) z roku 2008, přičemž většina poznámek se omezuje na onemocnění polycythaemia vera (PV). Při analýze hlavních kritérií poznamenáváme, že existují pacienti s PV, jejichž erytrocytóza může být dokumentována pouze měřením objemu erytrocytární masy a nikoli měřením koncentrace hemoglobinu nebo hematokritu. Probíráme reprodukovatelnost histopatologie pro diagnostiku různých stadií MPN, existenci normálních hladin EPO u pacientů s PV, specifitu růstu endogenních erytroidních kolonií (EEC) pro diagnózu PV a naše současné znalosti týkající se cytogenetiky a molekulární biologie PV a jiných MPN a jejich patofyziologie. Rovněž analyzujeme různé prognostické ukazatele morbidity (trombóza) a mortality u PV – vysokou hladinu hematokritu, leukocytózu a procentuální zastoupení buněk s mutací JAK2V617F. V případě esenciální trombocytemie (ET) komentujeme rozlišení pravé ET a “časné PMF”. V závěru stručně shrnujeme obecně přijímaná doporučení European LeukemiaNet (ELN) pro léčbu Ph-negativní MPN na základě nové stratifikace rizika, na důkazech založené riziko kancerogeneze u hydroxyurey a racionální doporučení pro výběr konkrétních léků.
In this paper, we discuss some critical parts of the World Health Organization (WHO) 2008 criteria for classification of MPNs classification, with most of the remarks limited to polycythemia vera (PV). When analyzing the major criteria, we note that there are PV patients whose erythrocytosis can only be documented by red cell mass measurements and not by hemoglobin concentration or hematocrit measurements. We discuss the reproducibility of histopathology for the diagnosis of different stages of MPNs, the existence of normal EPO levels in PV patients, the specificity of Endogenous erythroid colony (EEC) growth for PV diagnosis and our current knowledge of the cytogenetics and molecular biology of PV and other MPNs and their pathophysiology. We also analyze various prognostic morbidity (thrombosis) and mortality markers in PV – high hematocrit level, leukocytosis and percentage of cells with the JAK2V617F mutation. In essential thrombocythemia (ET), we comment on the distinction of true ET and “early PMF”. At the end, we briefly summarize the generally accepted new risk stratification European Leukemia Network (ELN) treatment recommendations for Ph-negative MPNs, evidence-based risk of carcinogenesis for hydroxyurea and rational recommendations for the selection of individual drugs.
- Klíčová slova
- polycythaemia vera, esenciální trombocytopenie, diagnostická kritéria dle WHO 2008,
- MeSH
- biologické markery krev MeSH
- cytogenetické vyšetření normy MeSH
- diferenciální diagnóza MeSH
- erythropoetin krev MeSH
- esenciální trombocytemie diagnóza terapie MeSH
- financování organizované MeSH
- hematologické nádory diagnóza klasifikace MeSH
- hematologie normy MeSH
- Janus kinasa 2 genetika MeSH
- kostní dřeň patologie MeSH
- laboratorní medicína normy MeSH
- leukemie myeloidní chronická atypická BCR-ABL-negativní diagnóza genetika patologie MeSH
- lidé MeSH
- mezinárodní klasifikace nemocí MeSH
- myeloproliferativní poruchy diagnóza klasifikace patologie MeSH
- polycythaemia vera diagnóza genetika patologie MeSH
- primární myelofibróza diagnóza terapie MeSH
- prognóza MeSH
- vyšetřování kostní dřeně MeSH
- Check Tag
- lidé MeSH