Anaplastic large cell lymphoma (ALCL), an aggressive CD30-positive T-cell lymphoma, comprises systemic anaplastic lymphoma kinase (ALK)-positive, and ALK-negative, primary cutaneous and breast implant-associated ALCL. Prognosis of some ALCL subgroups is still unsatisfactory, and already in second line effective treatment options are lacking. To identify genes defining ALCL cell state and dependencies, we here characterize super-enhancer regions by genome-wide H3K27ac ChIP-seq. In addition to known ALCL key regulators, the AP-1-member BATF3 and IL-2 receptor (IL2R)-components are among the top hits. Specific and high-level IL2R expression in ALCL correlates with BATF3 expression. Confirming a regulatory link, IL-2R-expression decreases following BATF3 knockout, and BATF3 is recruited to IL2R regulatory regions. Functionally, IL-2, IL-15 and Neo-2/15, a hyper-stable IL-2/IL-15 mimic, accelerate ALCL growth and activate STAT1, STAT5 and ERK1/2. In line, strong IL-2Rα-expression in ALCL patients is linked to more aggressive clinical presentation. Finally, an IL-2Rα-targeting antibody-drug conjugate efficiently kills ALCL cells in vitro and in vivo. Our results highlight the importance of the BATF3/IL-2R-module for ALCL biology and identify IL-2Rα-targeting as a promising treatment strategy for ALCL.
- MeSH
- anaplastický velkobuněčný lymfom farmakoterapie genetika metabolismus patologie MeSH
- antigen Ki-1 genetika metabolismus MeSH
- imunokonjugáty farmakologie MeSH
- interleukin-15 farmakologie MeSH
- interleukin-2 farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- receptor interleukinu-2 - alfa-podjednotka genetika imunologie metabolismus MeSH
- receptory interleukinu-2 genetika imunologie metabolismus MeSH
- regulace genové exprese u nádorů MeSH
- regulační oblasti nukleových kyselin MeSH
- represorové proteiny genetika metabolismus MeSH
- signální transdukce účinky léků MeSH
- transkripční faktory bZIP genetika metabolismus MeSH
- viabilita buněk účinky léků MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Immature B cells are susceptible to apoptosis due to ligation of surface immunoglobulin receptors. The WEHI 231 cell line represents a useful model to study the mode of action of factors preventing apoptosis. In this work we investigated the protective effects of multi-species lactoferrins in anti-mouse Ig-induced WEHI 231 cell death. Bovine milk-derived lactoferrin (bLF), recombinant human lactoferrin expressed in Chinese hamster ovary cells - rhLF(CHO) or in human endothelial kidney cells - rhLF(HEK), and recombinant mouse lactoferrin expressed in Chinese hamster ovary cells - rmLF(CHO), were used. Goat-anti-mouse Ig antibodies were used to induce cell apoptosis. Survival of WEHI 231 cells in culture was measured using the colorimetric MTT method. Expression of signalling molecules and subunits of interleukin 2 receptor was determined by the RT PCR method. The results showed that anti-mouse Ig antibodies inhibited cell growth in a dose-dependent manner. The lactoferrins alone had no effect on the cell survival. The cells exposed to LFs, prior to anti-Ig treatment, were rescued to a significant degree from cell death. Determination of the signalling molecule expression revealed almost complete suppression of caspase-3 and NF-κB1 by bLF in untreated cells, as well as deep suppression of caspase-3, block of Fas, and 4-fold increase of NF-κB1 in cells incubated with bLF prior to anti-Ig treatment. In addition, differential changes in the expression of interleukin 2 subunits upon bLF treatment were found, indicating a process of cell differentiation. In conclusion, we showed that LF-induced cell differentiation in immature B-cell line WEHI 231 was correlated with partial protection of the cells from anti-Ig-induced cell death.
- MeSH
- buněčná diferenciace účinky léků MeSH
- buněčná smrt účinky léků MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- křečci praví MeSH
- laktoferrin farmakologie MeSH
- lidé MeSH
- myši MeSH
- podjednotky proteinů metabolismus MeSH
- protilátky farmakologie MeSH
- receptory interleukinu-2 metabolismus MeSH
- signální transdukce účinky léků MeSH
- skot MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- myši MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with "sarcoidosis-associated" genes. Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry. Patient's BAL cells expressed higher mRNA T-bet levels than those of controls (mean ± sd fold change 3.64 ± 1.72; p = 0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p > 0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p < 0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes. In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.
- MeSH
- bronchoalveolární lavážní tekutina chemie cytologie MeSH
- chemokin CCL5 genetika metabolismus MeSH
- dospělí MeSH
- exprese genu MeSH
- interferon gama genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické uzliny metabolismus MeSH
- messenger RNA metabolismus MeSH
- plíce metabolismus MeSH
- plicní sarkoidóza genetika imunologie metabolismus MeSH
- proteiny T-boxu metabolismus MeSH
- receptory chemokinů genetika metabolismus MeSH
- receptory CXCR3 genetika metabolismus MeSH
- receptory interleukinu-2 genetika metabolismus MeSH
- Th1 buňky imunologie metabolismus MeSH
- upregulace MeSH
- virové receptory genetika metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
