Hereditary haemorrhagic telangiectasia (HHT) exhibits considerable phenotypic heterogeneity. Therefore, precise mutation screening and evaluation of patient risk must be determined in every HHT family. We present an HHT-2 case with an initial life-threatening bleeding episode that led to identification of a relatively large HHT family. Exome sequencing of the family members determined HHT-associated ACVRL1C1120T variant resulting in Arg374Trp substitution at the Ser/Thr-kinase domain region. The affected members display typical epistaxis symptomatology from early childhood resulting in sideropoenia. In addition, the HHT patients also displayed dermatology findings such as facial teleangiectasias and trunk/limb white spots representing post-inflammatory hypopigmentation. Interestingly, co-segregating with modifying cytochrome P450 (CYP2C) variant in the HHT patients led to NSAID intolerance marked by increased frequency of bleeding episodes. No arterial-venous malformation of the visceral organs and brain or association with cancer were observed. The heterogeneity of clinical presentation and the role of other variants support the need of regular patient monitoring and development of a nation-wide patient registry.

• MeSH
• cytochrom P450 CYP2C9 genetika   MeSH
• epistaxe MeSH
• hereditární hemoragická teleangiektazie genetika   MeSH
• lidé MeSH
• nádory kůže genetika   MeSH
• registrace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CYP2C9 protein, human MeSH Prohlížeč
• cytochrom P450 CYP2C9 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
• Názvy látek
• nádorové proteiny MeSH

• 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
• Názvy látek
• mikro RNA MeSH
• MIRN150 microRNA, human MeSH Prohlížeč
• MIRN155 microRNA, human MeSH Prohlížeč
• RNA nádorová MeSH

• Publikační typ
• časopisecké články 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
• Názvy látek
• mikro RNA MeSH
• Mirn155 microRNA, mouse MeSH Prohlížeč
• Myc protein, mouse MeSH Prohlížeč
• nádorový supresorový protein p53 MeSH
• onkogenní proteiny v-myb MeSH
• proto-oncogene protein Spi-1 MeSH Prohlížeč
• protoonkogenní proteiny c-myc MeSH
• protoonkogenní proteiny MeSH
• trans-aktivátory MeSH

Epigenetic 5-azacitidine (AZA) therapy of high-risk myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML) represents a promising, albeit not fully understood, approach. Hematopoietic transcription factor PU.1 is dynamically regulated by upstream regulatory element (URE), whose deletion causes downregulation of PU.1 leading to AML in mouse. In this study a significant group of the high-risk MDS patients, as well as MDS cell lines, displayed downregulation of PU.1 expression within CD34+ cells, which was associated with DNA methylation of the URE. AZA treatment in vitro significantly demethylated URE, leading to upregulation of PU.1 followed by derepression of its transcriptional targets and onset of myeloid differentiation. Addition of colony-stimulating factors (CSFs; granulocyte-CSF, granulocyte-macrophage-CSF and macrophage-CSF) modulated AZA-mediated effects on reprogramming of histone modifications at the URE and cell differentiation outcome. Our data collectively support the importance of modifying the URE chromatin structure as a regulatory mechanism of AZA-mediated activation of PU.1 and induction of the myeloid program in MDS.

• MeSH
• aktivace transkripce účinky léků   MeSH
• azacytidin farmakologie   terapeutické užití   MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• chromatin genetika   MeSH
• faktory stimulující kolonie farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA účinky léků   MeSH
• myelodysplastické syndromy farmakoterapie   genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• protinádorové antimetabolity farmakologie   terapeutické užití   MeSH
• protoonkogenní proteiny genetika   metabolismus   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• regulační oblasti nukleových kyselin účinky léků   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• trans-aktivátory genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azacytidin MeSH
• chromatin MeSH
• faktory stimulující kolonie MeSH
• protinádorové antimetabolity MeSH
• proto-oncogene protein Spi-1 MeSH Prohlížeč
• protoonkogenní proteiny MeSH
• trans-aktivátory 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
• Názvy látek
• proto-oncogene protein Spi-1 MeSH Prohlížeč
• protoonkogenní proteiny MeSH
• trans-aktivátory MeSH
• transkripční faktory GATA MeSH

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, APO2L) has been shown to induce apoptosis in a number of tumor cell lines as well as in some primary tumors whereas cells from most normal tissues are highly resistant to TRAIL-induced apoptosis. We have studied the susceptibility of primary malignant and normal bone marrow hematopoietic progenitors to TRAIL-induced apoptosis. Extracellular domain of human TRAIL with N-terminal His(6) tag (His-TRAIL, amino acids 95-281) was produced in E. coli and its apoptosis-inducing ability was compared with the leucine-zipper containing TRAIL, LZ-TRAIL. Both variants of TRAIL had the same apoptosis-inducing ability. Clonogenic progenitor assays showed that His-TRAIL significantly reduced the number of myeloid colonies (CFU-GM) and clusters from patients with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). His-TRAIL had no negative effect on the number of CFU-GM colonies and clusters derived from bone marrow cells of AML patients in complete remission, and lymphoma patients without bone marrow involvement, as well as those derived from normal cord blood cells. Moreover, we found that normal human stem cells treated with high doses of His-TRAIL maintain a repopulating potential when transplanted into NOD/SCID mice. To conclude, our data document that TRAIL does not affect normal human hematopoiesis but suppresses the growth of early primary leukemia and myelodysplasia progenitors.

• MeSH
• akutní nemoc MeSH
• analýza kolonii tvořících jednotek MeSH
• apoptóza účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky K562 účinky léků   MeSH
• hematopoetické kmenové buňky účinky léků   MeSH
• HL-60 buňky účinky léků   MeSH
• inhibitory růstu farmakologie   MeSH
• Jurkat buňky účinky léků   MeSH
• kultivované buňky účinky léků   MeSH
• leucinové zipy MeSH
• lidé MeSH
• membránové glykoproteiny chemie   genetika   farmakologie   MeSH
• myelodysplastické syndromy patologie   MeSH
• myeloidní buňky účinky léků   MeSH
• myeloidní leukemie patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buňky kultivované účinky léků   MeSH
• nádorové kmenové buňky účinky léků   MeSH
• nehodgkinský lymfom patologie   MeSH
• peptidové fragmenty chemie   genetika   farmakologie   MeSH
• přežívání štěpu MeSH
• protinádorové látky farmakologie   MeSH
• rekombinantní fúzní proteiny chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• terciární struktura proteinů MeSH
• testy nádorových kmenových buněk MeSH
• TNF-alfa chemie   genetika   farmakologie   MeSH
• transplantace hematopoetických kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• His-TRAIL protein, recombinant MeSH Prohlížeč
• inhibitory růstu MeSH
• LZ-TRAIL protein, recombinant MeSH Prohlížeč
• membránové glykoproteiny MeSH
• peptidové fragmenty MeSH
• protinádorové látky MeSH
• rekombinantní fúzní proteiny MeSH
• TNF-alfa MeSH

Tumour progression is dependent on the formation of new vessels in tumour tissue. Tumour cells produce a variety of factors that influence vessel growth and maintenance both in tumour and tumour-adjacent tissues. Angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their tyrosine kinase receptor Tie-2 have been shown to play an important role in the processes of growth and remodelling of normal as well as tumour vessels. We studied gene expression of the angiogenic factors Ang-1 and Ang-2 and of their tyrosine kinase receptor Tie-2 in the tumour and non-tumour tissues of mice bearing the experimental melanoma B16. Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR we measured Ang-1, Ang-2 and Tie-2 mRNA levels in the tumour, bone marrow, liver and spleen. Melanoma tissue overexpressed Ang-2 mRNA compared with spleen, liver and bone marrow of normal mice, suggesting its role during melanoma progression. On the other hand, there was a significant decrease in Ang-2 mRNA level in bone marrow cells collected on days 5 and 10 of tumour growth compared with the expression of Ang-2 mRNA in the bone marrow of normal mice and those collected on days 15 and 20 of tumour growth. These data demonstrate, for the first time, an ectopic effect of the tumour on the gene coding for an angiogenic factor, and also suggest that tumour growth may influence angiogenesis and/or vasculogenesis in distant organs.

• MeSH
• angiopoetin-1 MeSH
• angiopoetin-2 MeSH
• játra metabolismus   MeSH
• melanom experimentální metabolismus   MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory kůže metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• progrese nemoci MeSH
• proteiny genetika   metabolismus   MeSH
• receptor TIE-2 MeSH
• slezina metabolismus   MeSH
• transplantace nádorů MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• angiopoetin-1 MeSH
• angiopoetin-2 MeSH
• Angpt1 protein, mouse MeSH Prohlížeč
• membránové glykoproteiny MeSH
• messenger RNA MeSH
• proteiny MeSH
• receptor TIE-2 MeSH
• tyrosinkinasové receptory MeSH

We identified a subset of genes involved in chromatin remodeling whose mRNA expression changes in differentiating mouse erythroleukemia (MEL) cells. We furthermore tested their mRNA expression patterns in normal and malignant CD34+ bone marrow cells. SMARCA5, imitation switch gene homologue, was rapidly silenced during in vitro erythroid differentiation of MEL cells whereas it was up-regulated in CD34+ hematopoietic progenitors of acute myeloid leukemia (AML) patients. Moreover, SMARCA5 mRNA levels decreased in AML CD34+ progenitors after the patients achieved complete hematologic remission. We detected high levels of SMARCA5 mRNA in murine bone marrow and spleen and monitored its expression in these hematopoietic tissues during accelerated hematopoiesis following hemolytic anemia induced by phenylhydrazine. SMARCA5 expression levels decreased after the onset of accelerated erythropoiesis. Our data suggest that both in vitro and in vivo induction of differentiation is followed by down-regulation of SMARCA5 expression. In CD34+ AML progenitors over-expression of SMARCA5 may thus dysregulate the genetic program required for normal differentiation.

• MeSH
• akutní erytroblastická leukemie genetika   metabolismus   patologie   MeSH
• akutní nemoc MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• chromatin metabolismus   MeSH
• DNA-topoisomerasy typu II biosyntéza   genetika   MeSH
• erytroidní prekurzorové buňky metabolismus   patologie   MeSH
• fenylhydraziny toxicita   MeSH
• hematopoetické kmenové buňky metabolismus   patologie   MeSH
• hematopoéza genetika   MeSH
• hemolytické anemie chemicky indukované   metabolismus   patologie   MeSH
• kostní dřeň metabolismus   patologie   MeSH
• lidé MeSH
• messenger RNA biosyntéza   MeSH
• myeloidní leukemie genetika   metabolismus   patologie   MeSH
• myši inbrední C3H MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádorové kmenové buňky metabolismus   patologie   MeSH
• nádorové proteiny biosyntéza   genetika   MeSH
• proteiny s vysokou pohyblivostí biosyntéza   genetika   MeSH
• regulace genové exprese u leukemie * MeSH
• RNA nádorová biosyntéza   MeSH
• slezina metabolismus   patologie   MeSH
• stanovení celkové genové exprese MeSH
• subtrakční technika MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH
• DNA-topoisomerasy typu II MeSH
• fenylhydraziny MeSH
• messenger RNA MeSH
• nádorové proteiny MeSH
• phenylhydrazine MeSH Prohlížeč
• proteiny s vysokou pohyblivostí MeSH
• RNA nádorová MeSH