NPM-ALK Dotaz Zobrazit nápovědu
Genomic stability is crucial for cell life and transmitting genetic material is one of the primary tasks of the cell. The cell needs to be able to recognize any possible error and quickly repair it, and thus, cells have developed several mechanisms to detect DNA damage and promote repair during evolution. The DNA damage response (DDR) and DNA repair pathways ensure the control of possible errors that could impair the duplication of genetic information and introduce variants in the DNA. Endogenous and exogenous factors compromise genomic stability and cause dysregulation in the DDR and DNA repair pathways. Cancer cells often impair these mechanisms to overcome cellular barriers (cellular senescence and/or apoptosis), leading to malignancy. NPM (nucleophosmin)-ALK (anaplastic lymphoma kinase) is an oncogenic tyrosine kinase that is involved in the development of anaplastic large cell lymphoma (ALCL). NPM-ALK is known to be involved in the activation of proliferative and anti-apoptotic signaling pathways. New evidence reveals that NPM-ALK translocation also impairs the ability of cells to maintain the genomic stability through both DDR and DNA repair pathways. This review aims to highlight the role of the oncogenic tyrosine kinase NPM-ALK in the cell, and pointing to new possible therapeutic strategies.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL.
- Publikační typ
- časopisecké články MeSH
Anaplastic large cell lymphoma (ALCL) represents a heterogeneous group of malignant lymphoproliferative diseases with a consistent expression of the cytokine receptor CD30. ALCL is frequently associated with a NPM/ALK fusion gene which is found in up to 75% of pediatric ALCLs. Real-time quantitative RT-PCR (RQ-RT-PCR) of NPM/ALK and CD30 gene expression was employed to analyze minimal residual disease (MRD) in 10 patients with NPM/ALK positive ALCL in 79 follow-up bone marrow (BM) and/or peripheral blood (PB) samples. In all BM samples from relapses and/or closely before a relapse, BM samples revealed NPM/ALK and CD30 positivity in at least one of the iliac BM trephines. Five out of nine relapses were preceded or were accompanied by minimally half log increased NPM/ALK levels in the BM. We found that RQ-RT-PCR of the CD30 expression is not suitable for MRD detection--only two relapses were accompanied by an increase of the CD30 level above a level which was detected in BM/PB samples from healthy individuals. RQ-RT-PCR of NPM/ALK expression is a promising and rapid approach for monitoring MRD.
- MeSH
- anaplastický velkobuněčný lymfom genetika MeSH
- antigen Ki-1 genetika MeSH
- dítě MeSH
- dospělí MeSH
- exprese genu MeSH
- financování organizované MeSH
- lidé MeSH
- mladiství MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- polymerázová řetězová reakce MeSH
- předškolní dítě MeSH
- reziduální nádor genetika MeSH
- tyrosinkinasy genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- MeSH
- antigen Ki-1 genetika izolace a purifikace MeSH
- exprese genu genetika imunologie MeSH
- finanční podpora výzkumu jako téma MeSH
- financování organizované MeSH
- genetické markery genetika imunologie MeSH
- lidé MeSH
- lymfoproliferativní nemoci diagnóza genetika krev MeSH
- polymerázová řetězová reakce využití MeSH
- receptory cytokinové genetika imunologie MeSH
- reziduální nádor MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRβ. Blocking PDGFRβ kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRβ-driven human ALCL in vivo, we identify PDGFRβ as a driver of aggressive tumor growth. Mechanistically, PDGFRβ induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRβ as a novel biomarker and introduce PDGFRβ-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRβ or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.
- MeSH
- anaplastická lymfomová kináza MeSH
- anaplastický velkobuněčný lymfom * genetika patologie MeSH
- fosforylace MeSH
- karcinogeneze metabolismus MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- růstový faktor odvozený z trombocytů - receptor beta * metabolismus farmakologie MeSH
- signální transdukce MeSH
- transkripční faktor STAT3 * metabolismus MeSH
- transkripční faktor STAT5 * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- alektinib,
- MeSH
- adenokarcinom plic * diagnóza farmakoterapie terapie MeSH
- anaplastická lymfomová kináza * antagonisté a inhibitory MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- lidé MeSH
- piperidiny terapeutické užití MeSH
- rezistence k aktivovanému proteinu C MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
The majority of salivary gland carcinomas are characterized by recurrent gene fusions that proved highly valuable diagnostically, but only rarely of therapeutic impact. Most of these fusion-positive carcinomas belong to the low-grade or intermediate-grade biological category. To date, only 5 cases of salivary gland carcinomas carrying an oncogenic ALK fusion have been reported in 4 recent studies, but their phenotypic spectrum and their nosological classification remain uncharacterized. We herein describe in detail the clinicopathologic and molecular features of 4 ALK-fusion-positive salivary carcinomas and review previously reported cases to assess if they could be classified into a defined World Health Organization (WHO) category. Patients were 3 men and 1 woman aged from 67 to 79 years (median: 70 y). All tumors originated in the parotid gland. Their size ranged from 1.1 to 3 cm (mean, 2 cm). Three tumors were de novo high-grade salivary duct carcinomas (SDCs) and 1 was a low-grade intercalated-type intraductal carcinoma. Histologically, high-grade tumors were predominantly solid, composed of intimately admixed basal (CK5+, androgen-) and luminal (CK5-, androgen+) components. The remarkable basal component showed squamoid basophilic pattern imparting an adenosquamous-like appearance in all cases. Conventional apocrine intraductal high-grade carcinoma was noted in 1 case. Prominent intraductal growth of the solid basal component (highlighted by p63 staining) was seen in all cases. The tumor cells expressed CK7 (3/3), mammaglobin (3/3, 1 focal), GATA3 (3/3, 1 focal), variably CK5 (3/3), and focally the androgen receptor (1/3), but lacked expression of HER2/neu, SOX10, MUC4, TTF1, S100, and Napsin A. The low-grade tumor showed classic histologic and immunophenotypic features of intercalated-type noninvasive intraductal carcinoma. Molecular profiling showed rearrangements involving exon 20 of ALK in all cases, confirmed by ALK immunohistochemistry (IHC and FISH). The fusion partner was EML4 (n=2) and STRN (n=1) in high-grade tumors and EML4 in the intraductal carcinoma. Two patients with high-grade tumors developed progressive disease (1 died at 9 mo; 1 alive under palliative therapy at 5 mo). This series and a review of 5 published cases indicate that ALK rearrangements characterize 2 distinct subsets of salivary gland carcinomas in the spectrum of high-grade androgen-poor, basal-like SDC (total reported: 5 cases) and low-grade intercalated-type intraductal carcinomas (4 cases). Given the therapeutic relevance of ALK fusions, inclusion of ALK IHC in any atypical-looking or androgen-poor SDC and in high-grade adenocarcinoma-not otherwise specified is recommended. Absence of aberrant ALK expression in genetically characterized secretory (n=15) and intraductal (n=9) carcinomas lacking ALK fusions underlines the value of ALK IHC as a diagnostic screening method for identifying potential cases.
Neuroblastic tumours exhibit heterogeneity, which results in different therapeutic outcomes. Neuroblastoma is categorized into three major risk groups (low, intermediate, high risk). Recent identification of new genes raised the possibility of new biomarkers to identify sub-risk groups. In this retrospective cross-sectional study, we aimed to assess new biomarkers defining the ultra-high-risk subgroup within the high-risk group that differ in clinical situation with very bad prognosis. Twenty-five low- and 29 high-risk groups of patients were analysed for their expression of ALK, ATRX, HIF1a, HIF2a (EPAS), H2AFX, and ETV5 genes at the RNA level. Immunohistochemistry was performed to confirm the protein expression level of ALK. The risk group of patients was determined according to the International Neuroblastoma Risk Group Stratification System. Spearman correlation analysis and Mann-Whitney-U nonparametric test were used to assess the importance of expression levels among the groups. P < 0.05 was considered as significant. Sensitivity of the results was checked by ROC curve analysis. All analysed genes were found to be highly expressed in the high-risk group compared to the low-risk group, except for ETV5. When the ultra-high-risk and highrisk groups were compared, ALK was found to be highly expressed in the ultra-high-risk group. Our results show that ALK may be a candidate gene whose mRNA expression levels can distinguish the ultrahigh- risk subgroup of patients in the high-risk group of patients with non-familial neuroblastoma.
- MeSH
- anaplastická lymfomová kináza genetika MeSH
- imunohistochemie MeSH
- lidé MeSH
- neuroblastom * genetika MeSH
- průřezové studie MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Nemalobuněčné karcinomy plic (NSCLC) s pozitivitou mutací ALK byly poprvé popsány v roce 2007. V léčbě pacientů s těmito mutacemi jsou stěžejní inhibitory ALK (anaplastická lymfomová kináza). Cílem těchto léků jsou nádory s přítomností přestavby genu ALK, nejčastěji s fúzním genem EML4-ALK. Lorlatinib je selektivní inhibitor ALK 3. generace určený k léčbě nemocných s pokročilým NSCLC s pozitivitou ALK, u nichž došlo k progresi onemocnění po léčbě inhibitory ALK první a druhé generace.
- Klíčová slova
- lorlatinib,
- MeSH
- aminopyridiny terapeutické užití MeSH
- anaplastická lymfomová kináza antagonisté a inhibitory MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- laktamy terapeutické užití MeSH
- lidé MeSH
- nemalobuněčný karcinom plic farmakoterapie mortalita MeSH
- pyrazoly terapeutické užití MeSH
- Check Tag
- lidé MeSH
