- MeSH
- chronická lymfatická leukemie * diagnóza genetika patologie MeSH
- lidé MeSH
- lymfom z plášťových buněk * diagnóza genetika patologie MeSH
- mikro RNA MeSH
- nádorová transformace buněk MeSH
- nádorové biomarkery analýza MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Richter syndrome represents the transformation of the chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most frequently the diffuse large B-cell lymphoma (DLBCL). In this report we describe a patient with CLL, who developed a clonally-related pleomorphic highly-aggressive mantle cell lymphoma (MCL) after five cycles of a fludarabine-based second-line therapy for the first relapse of CLL. Molecular cytogenetic methods together with whole-exome sequencing revealed numerous gene alterations restricted to the MCL clone (apart from the canonical t(11;14)(q13;q32) translocation) including gain of one copy of ATM gene or emergence of TP53, CREBBP, NUP214, FUBP1 and SF3B1 gene mutations. Similarly, gene expression analysis revealed vast differences between the MCL and CLL transcriptome, including overexpression of cyclin D1, downregulation of cyclins D2 and D3, or downregulation of IL4R in the MCL clone. Backtracking analysis using quantitative PCR specifically detecting an MCL-restricted focal deletion of TP53 revealed that the pre-MCL clone appeared in the bone marrow and peripheral blood of the patient approximately 4 years before the clinical manifestation of MCL. Both molecular cytogenetic and sequencing data support the hypothesis of a slow development of the pre-MCL clone in parallel to CLL over several years, and thereby exclude the possibility that the transformation event occurred at the stage of the CLL relapse clone by mere t(11;14)(q13;q32) acquisition.
- MeSH
- chronická lymfatická leukemie genetika metabolismus patologie MeSH
- difúzní velkobuněčný B-lymfom genetika metabolismus patologie MeSH
- hybridizace in situ fluorescenční MeSH
- imunohistochemie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 11 MeSH
- lidské chromozomy, pár 14 MeSH
- lymfom z plášťových buněk genetika metabolismus patologie MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- translokace genetická MeSH
- ztráta heterozygozity MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
GATA-1 and PU.1 are two important hematopoietic transcription factors that mutually inhibit each other in progenitor cells to guide entrance into the erythroid or myeloid lineage, respectively. PU.1 controls its own expression during myelopoiesis by binding to the distal URE enhancer, whose deletion leads to acute myeloid leukemia (AML). We herein present evidence that GATA-1 binds to the PU.1 gene and inhibits its expression in human AML-erythroleukemias (EL). Furthermore, GATA-1 together with DNA methyl Transferase I (DNMT1) mediate repression of the PU.1 gene through the URE. Repression of the PU.1 gene involves both DNA methylation at the URE and its histone H3 lysine-K9 methylation and deacetylation as well as the H3K27 methylation at additional DNA elements and the promoter. The GATA-1-mediated inhibition of PU.1 gene transcription in human AML-EL mediated through the URE represents important mechanism that contributes to PU.1 downregulation and leukemogenesis that is sensitive to DNA demethylation therapy.
- MeSH
- akutní erytroblastická leukemie genetika patologie MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- buněčná diferenciace genetika MeSH
- DNA-(cytosin-5-)methyltransferasa genetika metabolismus MeSH
- genetická transkripce MeSH
- histony genetika MeSH
- lidé MeSH
- metylace DNA genetika MeSH
- promotorové oblasti (genetika) MeSH
- protoonkogenní proteiny biosyntéza genetika metabolismus MeSH
- regulace genové exprese u leukemie MeSH
- trans-aktivátory biosyntéza genetika metabolismus MeSH
- transkripční faktor GATA1 genetika metabolismus MeSH
- vazba proteinů MeSH
- zesilovače transkripce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
The transcription factor PU.1 and its inhibitory microRNA-155 (miR-155) are important regulators of B-cell differentiation. PU.1 downregulation coupled with oncogenic miR-155 upregulation has been reported in lymphoid malignancies; however, these data have not been studied across different subtypes in relation to clinical outcomes. We studied expression of miR-155 and PU.1 in the six most prevalent human B-cell lymphomas (n = 131) including aggressive (DLBCL, HL, MCL) and indolent (B-CLL/SLL, MZL, FL) types. Levels of miR-155 and PU.1 inversely correlated in DLBCL, B-CLL/SLL, and FL tumor tissues. In HL tissues, an exceptionally high level of miR-155 was found in patients with unfavorable responses to first-line therapy and those who had shorter survival times. PU.1 downregulation was noted in B-CLL/SLL samples positive for the adverse prognostic markers CD38 and ZAP-70. Upregulation of miR-155 and downregulation of PU.1 expression are integral aspects of lymphoma biology that could mark aggressive behavior of some, but not all, lymphoma types.
- MeSH
- antigeny CD38 metabolismus MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom metabolismus mortalita MeSH
- mikro RNA biosyntéza MeSH
- nádorové biomarkery biosyntéza MeSH
- prevalence MeSH
- protein-tyrosinkináza ZAP-70 metabolismus MeSH
- protoonkogenní proteiny biosyntéza MeSH
- regulace genové exprese u nádorů * MeSH
- RNA nádorová biosyntéza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- trans-aktivátory biosyntéza 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
- časopisecké články MeSH
- práce podpořená grantem MeSH
CCCTC-binding factor (CTCF) can both activate as well as inhibit transcription by forming chromatin loops between regulatory regions and promoters. In this regard, Ctcf binding on non-methylated DNA and its interaction with the Cohesin complex results in differential regulation of the H19/Igf2 locus. Similarly, a role for CTCF has been established in normal hematopoietic development; however its involvement in leukemia remains elusive. Here, we show that Ctcf binds to the imprinting control region of H19/Igf2 in AML blasts. We also demonstrate that Smarca5, which also associates with the Cohesin complex, facilitates Ctcf binding to its target sites on DNA. Furthermore, Smarca5 supports Ctcf functionally and is needed for enhancer-blocking effect at ICR. We next asked whether CTCF and SMARCA5 control the expression of key hematopoiesis regulators. In normally differentiating myeloid cells both CTCF and SMARCA5 together with members of the Cohesin complex are recruited to the SPI1 gene, a key hematopoiesis regulator and leukemia suppressor. Due to DNA methylation, CTCF binding to the SPI1 gene is blocked in AML blasts. Upon AZA-mediated DNA demethylation of human AML blasts, CTCF and SMARCA5 are recruited to the -14.4 Enhancer of SPI1 gene and block its expression. Our data provide new insight into complex SPI1 gene regulation now involving additional key epigenetic factors, CTCF and SMARCA5 that control PU.1 expression at the -14.4 Enhancer.
- MeSH
- adenosintrifosfatasy genetika metabolismus MeSH
- akutní erytroblastická leukemie genetika metabolismus patologie MeSH
- akutní nemoc MeSH
- azacytidin farmakologie MeSH
- buňky K562 MeSH
- chromozomální proteiny, nehistonové genetika metabolismus MeSH
- epigeneze genetická * MeSH
- genomový imprinting MeSH
- HeLa buňky MeSH
- imunoblotting MeSH
- insulinu podobný růstový faktor II genetika metabolismus MeSH
- konfokální mikroskopie MeSH
- lidé MeSH
- metylace DNA účinky léků MeSH
- myeloidní leukemie genetika metabolismus patologie MeSH
- nádorové buněčné linie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- protoonkogenní proteiny genetika metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- represorové proteiny genetika metabolismus MeSH
- RNA dlouhá nekódující genetika metabolismus MeSH
- RNA interference MeSH
- trans-aktivátory genetika metabolismus MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Nucleosome movement is, at least in part, facilitated by ISWI ATPase Smarca5 (Snf2h). Smarca5 gene inactivation in mouse demonstrated its requirement at blastocyst stage; however its role at later stages is not completely understood. We herein determined nuclear distribution of Smarca5 and histone marks associated with actively transcribed and repressed chromatin structure in embryonic and adult murine tissues and in tumor cells. Confocal microscopy images demonstrate that Smarca5 is localized mainly in euchromatin and to lesser extent also in heterochromatin and nucleoli. Smarca5 heterozygous mice for a null allele display decreased levels of histone H3 modifications and defects in heterochromatin foci supporting role of Smarca5 as a key regulator of global chromatin structure.
- MeSH
- adenosintrifosfatasy genetika metabolismus MeSH
- blastocysta metabolismus MeSH
- buněčné jadérko metabolismus MeSH
- chromozomální proteiny, nehistonové genetika metabolismus MeSH
- euchromatin metabolismus MeSH
- heterochromatin metabolismus MeSH
- konfokální mikroskopie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- umlčování genů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
