Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

• MeSH
• anaplastická lymfomová kináza genetika   metabolismus   MeSH
• anaplastický velkobuněčný lymfom * genetika   metabolismus   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• Janus kinasy metabolismus   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• signální transdukce * genetika   MeSH
• transkripční faktor STAT3 genetika   MeSH
• transkripční faktory STAT metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• Janus kinasy MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 MeSH
• transkripční faktory STAT MeSH

Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.

• Klíčová slova
• ALCL, PDX, brigatinib, crizotinib, tyrosine kinase inhibitors,
• MeSH
• anaplastická lymfomová kináza MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   patologie   MeSH
• dítě MeSH
• heterografty MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• krizotinib farmakologie   terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * MeSH
• organofosforové sloučeniny farmakologie   terapeutické užití   MeSH
• tyrosinkinasové receptory terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anaplastická lymfomová kináza MeSH
• brigatinib MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• krizotinib MeSH
• organofosforové sloučeniny MeSH
• tyrosinkinasové receptory 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.

• Klíčová slova
• ALCL, Apoptosis, NPM-ALK, PDGFRβ, STAT3, STAT5A, STAT5B,
• 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
• Názvy látek
• anaplastická lymfomová kináza MeSH
• růstový faktor odvozený z trombocytů - receptor beta * MeSH
• STAT3 protein, human MeSH Prohlížeč
• transkripční faktor STAT3 * MeSH
• transkripční faktor STAT5 * MeSH

Histone deacetylases (HDACs) target acetylated lysine residues in histone and non-histone proteins. HDACs are implicated in the regulation of genomic stability, cell cycle, cell death and differentiation and thus critically involved in tumorigenesis. Further, HDACs regulate T-cell development and HDAC inhibitors (HDACis) have been approved for clinical use in some T-cell malignancies. Still, the exact targets and mechanisms of HDAC inhibition in cancer are understudied. We isolated tumor cell lines from a transgenic mouse model of anaplastic large cell lymphoma (ALCL), a rare T-cell lymphoma, and abrogated HDAC activity by treatment with the HDACis Vorinostat and Entinostat or Cre-mediated deletion of Hdac1. Changes in overall protein expression as well as histone and protein acetylation were measured following Hdac1 deletion or pharmacological inhibition using label-free liquid chromatography mass spectrometry (LC-MS/MS). We found changes in overall protein abundance and increased acetylation of histones and non-histone proteins, many of which were newly discovered and associated with major metabolic and DNA damage pathways. For non-histone acetylation, we mapped a total of 1204 acetylated peptides corresponding to 603 proteins, including chromatin modifying proteins and transcription factors. Hyperacetylated proteins were involved in processes such as transcription, RNA metabolism and DNA damage repair (DDR). The DDR pathway was majorly affected by hyperacetylation following HDAC inhibition. This included acetylation of H2AX, PARP1 and previously unrecognized acetylation sites in TP53BP1. Our data provide a comprehensive view of the targets of HDAC inhibition in malignant T cells with general applicability and could have translational impact for the treatment of ALCL with HDACis alone or in combination therapies.

• Klíčová slova
• ALCL, MS-275, SAHA, acetylomics, anaplastic large cell lymphoma, entinostat, histone deacetylase inhibitors, histone deacetylases, proteomics, vorinostat,
• MeSH
• acetylace MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   MeSH
• chromatografie kapalinová MeSH
• histondeacetylasy * metabolismus   MeSH
• histony metabolismus   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• myši MeSH
• tandemová hmotnostní spektrometrie MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondeacetylasy * MeSH
• histony MeSH
• kyseliny hydroxamové MeSH

Lymphomas of the breast are rare neoplasms that arise from breast lymphoid tissue and are characterised by neoplastic B or T cells. Breast lymphomas arising from B cells include, but are not limited to, diffuse large B cell lymphoma, follicular lymphoma, extra-nodal marginal zone lymphoma and Burkitt lymphoma. Anaplastic large cell lymphoma (ALCL) is of a T cell origin and both anaplastic lymphoma kinase (ALK)-positive and ALK-negative presentations have been noted in the breast. In addition, there is a more recently identified presentation of ALK-negative ALCL that arises around textured breast implants and is usually confined to a periprosthetic fibrous capsule. Here, we discuss the clinical presentations, histological and immunohistochemical features and treatment options for each type of primary breast lymphoma. We hope that this review will highlight the importance of the timely and accurate diagnosis of breast lymphoma in order to tailor the most appropriate treatment. We also wish to raise awareness of the breast implant-associated lymphomas, with the goal of stimulating work that will aid our understanding of their epidemiology and pathogenesis.

• Klíčová slova
• BIA-ALCL, breast implant lymphoma, breast implants, breast lymphoma, non-Hodgkin lymphoma,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• ALCL, Brg1, NPM-ALK,
• Publikační typ
• časopisecké články MeSH

Non-Hodgkin lymphoma (NHL) is the third most common malignancy diagnosed in children. The vast majority of paediatric NHL are either Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma (ALCL), or lymphoblastic lymphoma (LL). Multi-agent chemotherapy is used to treat all of these types of NHL, and survival is over 90% but the chemotherapy regimens are intensive, and outcomes are generally poor if relapse occurs. Therefore, targeted therapies are of interest as potential solutions to these problems. However, the major problem with all targeted agents is the development of resistance. Mechanisms of resistance are not well understood, but increased knowledge will facilitate optimal management strategies through improving our understanding of when to select each targeted agent, and when a combinatorial approach may be helpful. This review summarises currently available knowledge regarding resistance to targeted therapies used in paediatric anaplastic lymphoma kinase (ALK)-positive ALCL. Specifically, we outline where gaps in knowledge exist, and further investigation is required in order to find a solution to the clinical problem of drug resistance in ALCL.

• Klíčová slova
• anaplastic large cell lymphoma, chemotherapy, nucleophosmin1-anaplastic lymphoma kinase, paediatric cancer, resistance,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

• MeSH
• anaplastický velkobuněčný lymfom * farmakoterapie   genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mutace MeSH
• nádorové buněčné linie MeSH
• receptor Notch1 genetika   MeSH
• sekvenování exomu MeSH
• tyrosinkinasové receptory genetika   MeSH
• tyrosinkinasy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• NOTCH1 protein, human MeSH Prohlížeč
• receptor Notch1 MeSH
• tyrosinkinasové receptory MeSH
• tyrosinkinasy MeSH

Salivary gland carcinomas represent a heterogeneous group of poorly characterized head and neck tumors. The purpose of this study was to evaluate ALK gene and protein aberrations in a large, well-characterized cohort of these tumors. A total of 182 salivary gland carcinomas were tested for anaplastic lymphoma kinase (ALK) positivity by immunohistochemistry (IHC) using the cut-off of 10% positive cells. ALK positive tumors were subjected to FISH analysis and followed by hybrid capture-based next generation sequencing (NGS). Of the 182 tumors, 8 were ALK positive by IHC. Further analysis using hybrid capture NGS analysis revealed a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion in one case of intraductal carcinoma. Additional genomic analyses resulted in the detection of inactivating mutations in BRAF and TP53, as well as amplifications of ERBB2 and ALK. ALK rearrangements are a rare entity in salivary gland carcinomas. We identified a potentially targetable novel ALK fusion in an intraductal carcinoma of minor salivary glands.

• Klíčová slova
• Anaplastic lymphoma kinase, FISH, Immunohistochemistry, Intraductal carcinoma, Next generation sequencing, Salivary gland carcinoma,
• MeSH
• amplifikace genu MeSH
• anaplastická lymfomová kináza genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• intraduktální neinfiltrující karcinom enzymologie   genetika   patologie   MeSH
• karcinom enzymologie   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinných žláz enzymologie   genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ALK protein, human MeSH Prohlížeč
• anaplastická lymfomová kináza MeSH
• nádorové biomarkery MeSH

Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly altered. Dissociation of NPM heterooligomers may thus restore the proper localization and function of wild-type NPM. NSC348884 is supposed to act as a potent inhibitor of NPM oligomerization. The effect of NSC348884 on the NPM oligomerization was thoroughly examined by fluorescence lifetime imaging with utilization of FRET and by a set of immunoprecipitation and electrophoretic methods. Leukemia-derived cell lines and primary AML cells as well as cells transfected with fluorescently labeled NPM forms were investigated. Our results clearly demonstrate that NSC348884 does not inhibit formation of NPM oligomers neither in vivo nor in vitro. Instead, we document that NSC348884 cytotoxicity is rather associated with modified cell adhesion signaling. The cytotoxic mechanism of NSC348884 has therefore to be reconsidered.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• HEK293 buňky MeSH
• indoly farmakologie   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• leukemie farmakoterapie   genetika   metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nukleofosmin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• indoly MeSH
• jaderné proteiny MeSH
• NPM1 protein, human MeSH Prohlížeč
• NSC 348884 MeSH Prohlížeč
• nukleofosmin MeSH