Lambda interferons mediate antiviral immunity by inducing interferon-stimulated genes (ISGs) in epithelial tissues. A common variant rs368234815TT/∆G creating functional gene from an IFNL4 pseudogene is associated with the expression of major ISGs in the liver but impaired clearance of hepatitis C. To explain this, we compared Halo-tagged and non-tagged IFNL3 and IFNL4 signaling in liver-derived cell lines. Transfection with non-tagged IFNL3, non-tagged IFNL4 and Halo-tagged IFNL4 led to a similar degree of JAK-STAT activation and ISG induction; however, the response to transfection with Halo-tagged IFNL3 was lower and delayed. Transfection with non-tagged IFNL3 or IFNL4 induced no transcriptome change in the cells lacking either IL10R2 or IFNLR1 receptor subunits. Cytosolic overexpression of signal peptide-lacking IFNL3 or IFNL4 in wild type cells did not interfere with JAK-STAT signaling triggered by interferons in the medium. Finally, expression profile changes induced by transfection with non-tagged IFNL3 and IFNL4 were highly similar. These data do not support the hypothesis about IFNL4-specific non-canonical signaling and point out that functional studies conducted with tagged interferons should be interpreted with caution.
- MeSH
- buněčné linie MeSH
- buňky Hep G2 MeSH
- exprese genu MeSH
- genový knockout MeSH
- hepatocyty imunologie metabolismus MeSH
- interferonové regulační faktory genetika metabolismus MeSH
- interferony nedostatek genetika metabolismus MeSH
- interleukiny nedostatek genetika metabolismus MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- receptor interleukinu-10 - beta-podjednotka nedostatek genetika metabolismus MeSH
- receptory interferonů nedostatek genetika metabolismus MeSH
- rekombinantní proteiny genetika metabolismus MeSH
- signální transdukce MeSH
- transfekce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The karyotype of bone-marrow cells at the time of diagnosis is one of the most important prognostic factors in patients with myelodysplastic syndromes (MDS). In some cases, the acquisition of additional genetic aberrations (clonal evolution [CE]) associated with clinical progression may occur during the disease. We analyzed a cohort of 469 MDS patients using a combination of molecular cytogenomic methods to identify cryptic aberrations and to assess their potential role in CE. We confirmed CE in 36 (8%) patients. The analysis of bone-marrow samples with a combination of cytogenomic methods at diagnosis and after CE identified 214 chromosomal aberrations. The early genetic changes in the diagnostic samples were frequently MDS specific (17 MDS-specific/57 early changes). Most progression-related aberrations identified after CE were not MDS specific (131 non-MDS-specific/155 progression-related changes). Copy number neutral loss of heterozygosity (CN-LOH) was detected in 19% of patients. MDS-specific CN-LOH (4q, 17p) was identified in three patients, and probably pathogenic homozygous mutations were found in TET2 (4q24) and TP53 (17p13.1) genes. We observed a statistically significant difference in overall survival (OS) between the groups of patients divided according to their diagnostic cytogenomic findings, with worse OS in the group with complex karyotypes (P = .021). A combination of cytogenomic methods allowed us to detect many cryptic genomic changes and identify genes and genomic regions that may represent therapeutic targets in patients with progressive MDS.
- MeSH
- analýza přežití MeSH
- chromozomální aberace MeSH
- DNA vazebné proteiny genetika MeSH
- dospělí MeSH
- klonální evoluce * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- myelodysplastické syndromy klasifikace genetika patologie MeSH
- nádorový supresorový protein p53 genetika MeSH
- prognóza MeSH
- protoonkogenní proteiny genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ztráta heterozygozity 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
Deletion 20q is a recurrent abnormality in myeloid malignancies. In our previous study, we identified fusion of the additional sex combs-like 1 (ASXL1) and teashirt zinc finger homeobox 2 genes in a patient with myelodysplastic syndrome. The objective of this study was to determine the frequency of ASXL1 breakpoints in a cohort of 36 patients with deletion 20q as the sole cytogenetic aberration. A combination of molecular cytogenetic methods was used to confirm ASXL1 gene alterations in 19 of the 36 patients, and the determination of ASXL1 gene changes in patients with deletion 20q revealed clinical and prognostic impacts.
U nemocných s hematologickými malignitami je jedním z nejdůležitějších nálezů karyotyp buněk kostní dřeně v době stanovení diagnózy. Detekce klonálních chromosomových aberací v diagnostických vzorcích nejen potvrzuje neoplastický nebo premaligní proces, ale také poskytuje diagnostické a prognostické informace, které jsou důležité pro přesnou klasifikaci onemocnění a výběr vhodné terapie. Analýza karyoytypu v průběhu onemocnění slouží rovněž k monitorování úspěšnosti léčby. Tyto skutečnosti se odrážejí i v revidované klasifikaci WHO, v níž jsou pacienti často řazeni do různých diagnostických subtypů právě na základě nálezu specifických chromosomových a/nebo genetických změn. V posledních letech dále vzrůstá počet moderních léčebných přístupů, jež přímo či nepřímo cílí na genetické aberace přítomné v nádorových buňkách. Cytogenetická analýza doplněná o výsledky molekulárně cytogenetických metod tak i přes velký rozvoj nových sekvenačních technologií v posledních letech stále zůstává velmi důležitou součástí diagnostiky hematologických malignit.
In patients with hematological malignancies one of the most substantial findings is the karyotype of bone marrow cells at the time of diagnosis. The detection of clonal chromosome aberrations in diagnostic samples not only confirms a neoplastic or premalignant process but also provides important diagnostic and prognostic information essential for precise disease classification and choice of suitable therapy. Karyotype analysis during the disease course also allows monitoring of the treatment success reflected as well in the revised WHO classification where patients are often classified into the different diagnostic subtypes based on the finding of specific chromosome and/or genetic changes. Recently, also increases the number of advanced treatment approaches that directly or indirectly target the genetic aberrations present in tumor cells. Despite the large development of new sequencing technologies in recent years, cytogenetic analysis supplemented by the molecular cytogenetic methods still remains a very important part of diagnostics of hematological malignancies.
Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first-line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R-CHOP and R-cytarabine for newly diagnosed transplant-ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography-computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression-free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography-negativity independently correlated with progression-free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R-CHOP and R-cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.
- MeSH
- cyklofosfamid farmakologie terapeutické užití MeSH
- cytarabin farmakologie terapeutické užití MeSH
- doxorubicin farmakologie terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfom z plášťových buněk farmakoterapie patologie MeSH
- myší monoklonální protilátky farmakologie terapeutické užití MeSH
- prednison farmakologie terapeutické užití MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- vinkristin farmakologie terapeutické užití 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
