128 results on '"Katarzyna Piwocka"'
Search Results
2. Stemness properties of SSEA-4+ subpopulation isolated from heterogenous Wharton’s jelly mesenchymal stem/stromal cells
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Agnieszka Smolinska, Magdalena Chodkowska, Agata Kominek, Jakub Janiec, Katarzyna Piwocka, Dorota Sulejczak, and Anna Sarnowska
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mesenchymal stem/stromal cells ,SSEA-4 ,stemness ,pluripotent ,FACS ,MACs ,Biology (General) ,QH301-705.5 - Abstract
Background: High heterogeneity of mesenchymal stem/stromal cells (MSCs) due to different degrees of differentiation of cell subpopulations poses a considerable challenge in preclinical studies. The cells at a pluripotent-like stage represent a stem cell population of interest for many researchers worldwide, which is worthy of identification, isolation, and functional characterization. In the current study, we asked whether Wharton’s jelly-derived MSCs (WJ-MSCs) which express stage-specific embryonic antigen-4 (SSEA-4) can be considered as a pluripotent-like stem cell population.Methods: SSEA-4 expression in different culture conditions was compared and the efficiency of two cell separation methods were assessed: Magnetic Activated Cell Sorting (MACS) and Fluorescence Activated Cell Sorting (FACS). After isolation, SSEA-4+ cells were analyzed for the following parameters: the maintenance of the SSEA-4 antigen expression after cell sorting, stem cell-related gene expression, proliferation potential, clonogenicity, secretome profiling, and the ability to form spheres under 3D culture conditions.Results: FACS allowed for the enrichment of SSEA-4+ cell content in the population that lasted for six passages after sorting. Despite the elevated expression of stemness-related genes, SSEA-4+ cells neither differed in their proliferation and clonogenicity potential from initial and negative populations nor exhibited pluripotent differentiation repertoire. SSEA-4+ cells were observed to form smaller spheroids and exhibited increased survival under 3D conditions.Conclusion: Despite the transient expression of stemness-related genes, our findings could not fully confirm the undifferentiated pluripotent-like nature of the SSEA-4+ WJ-MSC population cultured in vitro. more...
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- 2024
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Catalog
3. Targeting integrated stress response with ISRIB combined with imatinib treatment attenuates RAS/RAF/MAPK and STAT5 signaling and eradicates chronic myeloid leukemia cells
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Wioleta Dudka, Grazyna Hoser, Shamba S. Mondal, Laura Turos-Korgul, Julian Swatler, Monika Kusio-Kobialka, Magdalena Wołczyk, Agata Klejman, Marta Brewinska-Olchowik, Agata Kominek, Milena Wiech, Marcin M. Machnicki, Ilona Seferynska, Tomasz Stoklosa, and Katarzyna Piwocka more...
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ISR ,ISRIB ,CML ,Myeloid leukemia ,TKI resistance ,STAT5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The integrated stress response (ISR) facilitates cellular adaptation to unfavorable conditions by reprogramming the cellular response. ISR activation was reported in neurological disorders and solid tumors; however, the function of ISR and its role as a possible therapeutic target in hematological malignancies still remain largely unexplored. Previously, we showed that the ISR is activated in chronic myeloid leukemia (CML) cells and correlates with blastic transformation and tyrosine kinase inhibitor (TKI) resistance. Moreover, the ISR was additionally activated in response to imatinib as a type of protective internal signaling. Here, we show that ISR inhibition combined with imatinib treatment sensitized and more effectively eradicated leukemic cells both in vitro and in vivo compared to treatment with single agents. The combined treatment specifically inhibited the STAT5 and RAS/RAF/MEK/ERK pathways, which are recognized as drivers of resistance. Mechanistically, this drug combination attenuated both interacting signaling networks, leading to BCR-ABL1- and ISR-dependent STAT5 activation. Consequently, leukemia engraftment in patient-derived xenograft mice bearing CD34+ TKI-resistant CML blasts carrying PTPN11 mutation responsible for hyperactivation of the RAS/RAF/MAPK and JAK/STAT5 pathways was decreased upon double treatment. This correlated with the downregulation of genes related to the RAS/RAF/MAPK, JAK/STAT5 and stress response pathways and was associated with lower expression of STAT5-target genes regulating proliferation, viability and the stress response. Collectively, these findings highlight the effect of imatinib plus ISRIB in the eradication of leukemic cells resistant to TKIs and suggest potential clinical benefits for leukemia patients with TKI resistance related to RAS/RAF/MAPK or STAT5 signaling. We propose that personalized treatment based on the genetic selection of patients carrying mutations that cause overactivation of the targeted pathways and therefore make their sensitivity to such treatment probable should be considered as a possible future direction in leukemia treatment. more...
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- 2022
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4. TIAR and FMRP shape pro-survival nascent proteome of leukemia cells in the bone marrow microenvironment
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Magdalena Wolczyk, Remigiusz Serwa, Agata Kominek, Agata Klejman, Jacek Milek, Marta Chwałek, Laura Turos-Korgul, Agata Charzyńska, Michal Dabrowski, Magdalena Dziembowska, Tomasz Skorski, Katarzyna Piwocka, and Paulina Podszywalow-Bartnicka more...
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Biochemistry ,Molecular biology ,Cancer ,Proteomics ,Science - Abstract
Summary: Chronic myeloid leukemia (CML) cells circulate between blood and bone marrow niche, representing different microenvironments. We studied the role of the two RNA-binding proteins, T-cell-restricted intracellular antigen (TIAR), and the fragile X mental retardation protein (FMRP) in the regulation of protein translation in CML cells residing in settings mimicking peripheral blood microenvironment (PBM) and bone marrow microenvironment (BMM). The outcomes showed how conditions shaped the translation process through TIAR and FMRP activity, considering its relevance in therapy resistance. The QuaNCAT mass-spectrometric approach revealed that TIAR and FMRP have a discrete modulatory effect on protein synthesis and thus affect distinct aspects of leukemic cells functioning in the hypoxic niche. In the BMM setup, FMRP impacted metabolic adaptation of cells and TIAR substantially supported the resistance of CML cells to translation inhibition by homoharringtonine. Overall, our results demonstrated that targeting post-transcriptional control should be considered when designing anti-leukemia therapeutic solutions. more...
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- 2023
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5. Multi-omics analyses of early liver injury reveals cell-type-specific transcriptional and epigenomic shift
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Maciej Migdał, Eugeniusz Tralle, Karim Abu Nahia, Łukasz Bugajski, Katarzyna Zofia Kędzierska, Filip Garbicz, Katarzyna Piwocka, Cecilia Lanny Winata, and Michał Pawlak
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Liver ,Hepatocytes ,Stellate cells ,Endothelial cells ,Chromatin ,Transcriptomics ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Results In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. Conclusion Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals. more...
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- 2021
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6. Detailed characterization of SARS-CoV-2-specific T and B cells after infection or heterologous vaccination
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Domenico Lo Tartaro, Annamaria Paolini, Marco Mattioli, Julian Swatler, Anita Neroni, Rebecca Borella, Elena Santacroce, Alessia Di Nella, Licia Gozzi, Stefano Busani, Michela Cuccorese, Tommaso Trenti, Marianna Meschiari, Giovanni Guaraldi, Massimo Girardis, Cristina Mussini, Katarzyna Piwocka, Lara Gibellini, Andrea Cossarizza, and Sara De Biasi more...
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SARS-CoV-2 ,antigen-specific response ,polyfunctionality ,T cells ,B cells ,cytokine ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The formation of a robust long-term antigen (Ag)-specific memory, both humoral and cell-mediated, is created following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Here, by using polychromatic flow cytometry and complex data analyses, we deeply investigated the magnitude, phenotype, and functionality of SARS-CoV-2-specific immune memory in two groups of healthy subjects after heterologous vaccination compared to a group of subjects who recovered from SARS-CoV-2 infection. We find that coronavirus disease 2019 (COVID-19) recovered patients show different long-term immunological profiles compared to those of donors who had been vaccinated with three doses. Vaccinated individuals display a skewed T helper (Th)1 Ag-specific T cell polarization and a higher percentage of Ag-specific and activated memory B cells expressing immunoglobulin (Ig)G compared to those of patients who recovered from severe COVID-19. Different polyfunctional properties characterize the two groups: recovered individuals show higher percentages of CD4+ T cells producing one or two cytokines simultaneously, while the vaccinated are distinguished by highly polyfunctional populations able to release four molecules, namely, CD107a, interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. These data suggest that functional and phenotypic properties of SARS-CoV-2 adaptive immunity differ in recovered COVID-19 individuals and vaccinated ones. more...
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- 2023
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7. Transcriptome profile of the sinoatrial ring reveals conserved and novel genetic programs of the zebrafish pacemaker
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Rashid Minhas, Henry Loeffler-Wirth, Yusra H. Siddiqui, Tomasz Obrębski, Shikha Vashisht, Karim Abu Nahia, Alexandra Paterek, Angelika Brzozowska, Lukasz Bugajski, Katarzyna Piwocka, Vladimir Korzh, Hans Binder, and Cecilia Lanny Winata more...
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Zebrafish ,Cardiac conduction system ,Pacemaker ,Sinoatrial node ,Sinoatrial ring ,RNA-seq ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results To characterize the molecular profile of the zebrafish sinoatrial ring (SAR) and elucidate the mechanism of pacemaker function, we utilized the transgenic line sqet33mi59BEt to isolate cells of the SAR of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases. more...
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- 2021
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8. Dysfunctional subsets of CD39+ T cells, distinct from PD-1+, driven by leukemic extracellular vesicles in myeloid leukemias
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Julian Swatler, Domenico Lo Tartaro, Rebecca Borella, Marta Brewinska-Olchowik, Annamaria Paolini, Anita Neroni, Laura Turos-Korgul, Milena Wiech, Ewa Kozlowska, Dominik Cysewski, Wioleta Grabowska-Pyrzewicz, Urszula Wojda, Grzegorz Basak, Rafael J. Argüello, Andrea Cossarizza, Sara De Biasi, and Katarzyna Piwocka more...
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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9. IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen
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Marta Libura, Emilia Bialopiotrowicz, Sebastian Giebel, Agnieszka Wierzbowska, Gail J. Roboz, Beata Piatkowska-Jakubas, Marta Pawelczyk, Patryk Gorniak, Katarzyna Borg, Magdalena Wojtas, Izabella Florek, Karolina Matiakowska, Bozena Jazwiec, Iwona Solarska, Monika Noyszewska-Kania, Karolina Piechna, Magdalena Zawada, Sylwia Czekalska, Zoriana Salamanczuk, Karolina Karabin, Katarzyna Wasilewska, Monika Paluszewska, Elzbieta Urbanowska, Justyna Gajkowska-Kulik, Grazyna Semenczuk, Justyna Rybka, Tomasz Wrobel, Anna Ejduk, Dariusz Kata, Sebastian Grosicki, Tadeusz Robak, Agnieszka Pluta, Agata Kominek, Katarzyna Piwocka, Karolina Pyziak, Agnieszka Sroka-Porada, Anna Wrobel, Agnieszka Przybylowicz, Marzena Wojtaszewska, Krzysztof Lewandowski, Lidia Gil, Agnieszka Piekarska, Wanda Knopinska, Lukasz Bolkun, Krzysztof Warzocha, Kazimierz Kuliczkowski, Tomasz Sacha, Grzegorz Basak, Wieslaw Wiktor Jedrzejczak, Jerzy Holowiecki, Przemysław Juszczynski, and Olga Haus more...
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Medicine ,Science - Abstract
Abstract Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2 +) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2 + patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2 + patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2 + NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant. more...
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- 2021
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10. Tunneling Nanotubes Facilitate Intercellular Protein Transfer and Cell Networks Function
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Laura Turos-Korgul, Marta Dorota Kolba, Piotr Chroscicki, Aleksandra Zieminska, and Katarzyna Piwocka
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intercellular protein transfer ,proteome ,cellular network ,tunneling nanotubes (TNT) ,SILAC mass spectrometry ,codeIT ,Biology (General) ,QH301-705.5 - Abstract
The past decade witnessed a huge interest in the communication machinery called tunneling nanotubes (TNTs) which is a novel, contact-dependent type of intercellular protein transfer (IPT). As the IPT phenomenon plays a particular role in the cross-talk between cells, including cancer cells as well as in the immune and nervous systems, it therefore participates in remodeling of the cellular networks. The following review focuses on the placing the role of tunneling nanotube-mediated protein transfer between distant cells. Firstly, we describe different screening methods used to study IPT including tunneling nanotubes. Further, we present various examples of TNT-mediated protein transfer in the immune system, cancer microenvironment and in the nervous system, with particular attention to the methods used to verify the transfer of individual proteins. more...
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- 2022
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11. Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection
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Milena Wiech, Piotr Chroscicki, Julian Swatler, Dawid Stepnik, Sara De Biasi, Michal Hampel, Marta Brewinska-Olchowik, Anna Maliszewska, Katarzyna Sklinda, Marek Durlik, Waldemar Wierzba, Andrea Cossarizza, and Katarzyna Piwocka more...
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COVID-19 ,long COVID ,post-acute COVID-syndrome (PACS) ,convalescents ,immune system ,T cell exhaustion/senescence ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Several COVID-19 convalescents suffer from the post-acute COVID-syndrome (PACS)/long COVID, with symptoms that include fatigue, dyspnea, pulmonary fibrosis, cognitive dysfunctions or even stroke. Given the scale of the worldwide infections, the long-term recovery and the integrative health-care in the nearest future, it is critical to understand the cellular and molecular mechanisms as well as possible predictors of the longitudinal post-COVID-19 responses in convalescent individuals. The immune system and T cell alterations are proposed as drivers of post-acute COVID syndrome. However, despite the number of studies on COVID-19, many of them addressed only the severe convalescents or the short-term responses. Here, we performed longitudinal studies of mild, moderate and severe COVID-19-convalescent patients, at two time points (3 and 6 months from the infection), to assess the dynamics of T cells immune landscape, integrated with patients-reported symptoms. We show that alterations among T cell subsets exhibit different, severity- and time-dependent dynamics, that in severe convalescents result in a polarization towards an exhausted/senescent state of CD4+ and CD8+ T cells and perturbances in CD4+ Tregs. In particular, CD8+ T cells exhibit a high proportion of CD57+ terminal effector cells, together with significant decrease of naïve cell population, augmented granzyme B and IFN-γ production and unresolved inflammation 6 months after infection. Mild convalescents showed increased naïve, and decreased central memory and effector memory CD4+ Treg subsets. Patients from all severity groups can be predisposed to the long COVID symptoms, and fatigue and cognitive dysfunctions are not necessarily related to exhausted/senescent state and T cell dysfunctions, as well as unresolved inflammation that was found only in severe convalescents. In conclusion, the post-COVID-19 functional remodeling of T cells could be seen as a two-step process, leading to distinct convalescent immune states at 6 months after infection. Our data imply that attenuation of the functional polarization together with blocking granzyme B and IFN-γ in CD8+ cells might influence post-COVID alterations in severe convalescents. However, either the search for long COVID predictors or any treatment to prevent PACS and further complications is mandatory in all patients with SARS-CoV-2 infection, and not only in those suffering from severe COVID-19. more...
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- 2022
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12. Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer
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Ewelina Szymańska, Paulina Nowak, Krzysztof Kolmus, Magdalena Cybulska, Krzysztof Goryca, Edyta Derezińska‐Wołek, Anna Szumera‐Ciećkiewicz, Marta Brewińska‐Olchowik, Aleksandra Grochowska, Katarzyna Piwocka, Monika Prochorec‐Sobieszek, Michał Mikula, and Marta Miączyńska more...
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CRC ,ESCRT ,immunogenic cell death ,synthetic lethality ,VPS4B ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers. more...
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- 2020
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13. TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment
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Bac Viet Le, Paulina Podszywalow-Bartnicka, Silvia Maifrede, Katherine Sullivan-Reed, Margaret Nieborowska-Skorska, Konstantin Golovine, Juo-Chin Yao, Reza Nejati, Kathy Q. Cai, Lisa Beatrice Caruso, Julian Swatler, Michal Dabrowski, Zhaorui Lian, Peter Valent, Elisabeth M. Paietta, Ross L. Levine, Hugo F. Fernandez, Martin S. Tallman, Mark R. Litzow, Jian Huang, Grant A. Challen, Daniel Link, Italo Tempera, Mariusz A. Wasik, Katarzyna Piwocka, and Tomasz Skorski more...
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PARP inhibitor resistance ,TGFβR signaling ,bone marrow microenvironment ,Biology (General) ,QH301-705.5 - Abstract
Summary: Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis. more...
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- 2020
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14. Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells
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Jaroslaw Cendrowski, Marta Kaczmarek, Michał Mazur, Katarzyna Kuzmicz-Kowalska, Kamil Jastrzebski, Marta Brewinska-Olchowik, Agata Kominek, Katarzyna Piwocka, and Marta Miaczynska
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endocytosis ,copii trafficking ,autophagy ,erythroid differentiation ,splicing variants ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Intracellular transport undergoes remodeling upon cell differentiation, which involves cell type-specific regulators. Bone morphogenetic protein 2-inducible kinase (BMP2K) has been potentially implicated in endocytosis and cell differentiation but its molecular functions remained unknown. We discovered that its longer (L) and shorter (S) splicing variants regulate erythroid differentiation in a manner unexplainable by their involvement in AP-2 adaptor phosphorylation and endocytosis. However, both variants interact with SEC16A and could localize to the juxtanuclear secretory compartment. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system that controls the distribution of SEC16A and SEC24B as well as SEC31A abundance at COPII assemblies. Finally, we found L to promote and S to restrict autophagic degradation and erythroid differentiation. Hence, we propose that BMP2K-L and BMP2K-S differentially regulate abundance and distribution of COPII assemblies as well as autophagy, possibly thereby fine-tuning erythroid differentiation. more...
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- 2020
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15. Comparison of Differentiation Pattern and WNT/SHH Signaling in Pluripotent Stem Cells Cultured under Different Conditions
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Barbara Świerczek-Lasek, Damian Dudka, Damian Bauer, Tomasz Czajkowski, Katarzyna Ilach, Władysława Streminska, Agata Kominek, Katarzyna Piwocka, Maria A. Ciemerych, and Karolina Archacka
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pluripotent stem cells ,culture conditions ,differentiation ,WNT signaling ,SHH signaling ,Cytology ,QH573-671 - Abstract
Pluripotent stem cells (PSCs) are characterized by the ability to self-renew as well as undergo multidirectional differentiation. Culture conditions have a pivotal influence on differentiation pattern. In the current study, we compared the fate of mouse PSCs using two culture media: (1) chemically defined, free of animal reagents, and (2) standard one relying on the serum supplementation. Moreover, we assessed the influence of selected regulators (WNTs, SHH) on PSC differentiation. We showed that the differentiation pattern of PSCs cultured in both systems differed significantly: cells cultured in chemically defined medium preferentially underwent ectodermal conversion while their endo- and mesodermal differentiation was limited, contrary to cells cultured in serum-supplemented medium. More efficient ectodermal differentiation of PSCs cultured in chemically defined medium correlated with higher activity of SHH pathway while endodermal and mesodermal conversion of cells cultured in serum-supplemented medium with higher activity of WNT/JNK pathway. However, inhibition of either canonical or noncanonical WNT pathway resulted in the limitation of endo- and mesodermal conversion of PSCs. In addition, blocking WNT secretion led to the inhibition of PSC mesodermal differentiation, confirming the pivotal role of WNT signaling in this process. In contrast, SHH turned out to be an inducer of PSC ectodermal, not mesodermal differentiation. more...
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- 2021
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16. MLL-AF9 leukemias are sensitive to PARP1 inhibitors combined with cytotoxic drugs
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Silvia Maifrede, Esteban Martinez, Margaret Nieborowska-Skorska, Daniela Di Marcantonio, Michael Hulse, Bac Viet Le, Huaqing Zhao, Katarzyna Piwocka, Italo Tempera, Stephen M. Sykes, and Tomasz Skorski more...
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Specialties of internal medicine ,RC581-951 - Published
- 2017
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17. Stimulators of mineralization limit the invasive phenotype of human osteosarcoma cells by a mechanism involving impaired invadopodia formation.
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Anna Cmoch, Paulina Podszywalow-Bartnicka, Malgorzata Palczewska, Katarzyna Piwocka, Patrick Groves, and Slawomir Pikula
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Medicine ,Science - Abstract
BackgroundOsteosarcoma (OS) is a highly aggressive bone cancer affecting children and young adults. Growing evidence connects the invasive potential of OS cells with their ability to form invadopodia (structures specialized in extracellular matrix proteolysis).ResultsIn this study, we tested the hypothesis that commonly used in vitro stimulators of mineralization limit the invadopodia formation in OS cells. Here we examined the invasive potential of human osteoblast-like cells (Saos-2) and osteolytic-like (143B) OS cells treated with the stimulators of mineralization (ascorbic acid and B-glycerophosphate) and observed a significant difference in response of the tested cells to the treatment. In contrast to 143B cells, osteoblast-like cells developed a mineralization phenotype that was accompanied by a decreased proliferation rate, prolongation of the cell cycle progression and apoptosis. On the other hand, stimulators of mineralization limited osteolytic-like OS cell invasiveness into collagen matrix. We are the first to evidence the ability of 143B cells to degrade extracellular matrix to be driven by invadopodia. Herein, we show that this ability of osteolytic-like cells in vitro is limited by stimulators of mineralization.ConclusionsOur study demonstrates that mineralization competency determines the invasive potential of cancer cells. A better understanding of the molecular mechanisms by which stimulators of mineralization regulate and execute invadopodia formation would reveal novel clinical targets for treating osteosarcoma. more...
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- 2014
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18. The role of nibrin in doxorubicin-induced apoptosis and cell senescence in Nijmegen Breakage Syndrome patients lymphocytes.
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Olga Alster, Anna Bielak-Zmijewska, Grazyna Mosieniak, Maria Moreno-Villanueva, Wioleta Dudka-Ruszkowska, Aleksandra Wojtala, Monika Kusio-Kobiałka, Zbigniew Korwek, Alexander Burkle, Katarzyna Piwocka, Jan K Siwicki, and Ewa Sikora more...
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Medicine ,Science - Abstract
Nibrin plays an important role in the DNA damage response (DDR) and DNA repair. DDR is a crucial signaling pathway in apoptosis and senescence. To verify whether truncated nibrin (p70), causing Nijmegen Breakage Syndrome (NBS), is involved in DDR and cell fate upon DNA damage, we used two (S4 and S3R) spontaneously immortalized T cell lines from NBS patients, with the founding mutation and a control cell line (L5). S4 and S3R cells have the same level of p70 nibrin, however p70 from S4 cells was able to form more complexes with ATM and BRCA1. Doxorubicin-induced DDR followed by cell senescence could only be observed in L5 and S4 cells, but not in the S3R ones. Furthermore the S3R cells only underwent cell death, but not senescence after doxorubicin treatment. In contrary to doxorubicin treatment, cells from all three cell lines were able to activate the DDR pathway after being exposed to γ-radiation. Downregulation of nibrin in normal human vascular smooth muscle cells (VSMCs) did not prevent the activation of DDR and induction of senescence. Our results indicate that a substantially reduced level of nibrin or its truncated p70 form is sufficient to induce DNA-damage dependent senescence in VSMCs and S4 cells, respectively. In doxorubicin-treated S3R cells DDR activation was severely impaired, thus preventing the induction of senescence. more...
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- 2014
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19. Low interleukin-8 level predicts the occurrence of the postpericardiotomy syndrome.
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Maria Jaworska-Wilczyńska, Adriana Magalska, Katarzyna Piwocka, Piotr Szymański, Mariusz Kuśmierczyk, Maria Wąsik, and Tomasz Hryniewiecki
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Medicine ,Science - Abstract
AIMS: The objective of this study was to investigate inflammatory markers of the postpericardiotomy syndrome (PPS) and to determine individuals prone to develop the PPS. METHODS AND RESULTS: The study included 75 patients with a stable coronary disease that had underwent coronary artery bypass surgery. Serum samples were collected prior to the surgery and on the 5th day after the operation, to measure the concentration of IL-8, IL-6, IL-1β, IL-10, TNF, IL-12p70. All included patients were screened for the PPS before discharge from the hospital and 6 months after the surgery. The 49 patients developed the PPS (65.4%), among them 42 (56%) patients had pleural effusion, and 23 (31%) had pericardial effusion. The cytokine analysis has shown an inverse correlation between IL-8 concentration before the surgery, and the occurrence of the PPS (p = 0.026). There were also positive correlations between the magnitude of increase of IL-8 and IL-1β concentrations on the 5th day after the surgery and the occurrence of the PPS (p = 0.006 and p = 0.049 respectively). Multivariate analysis revealed IL-8 concentration before surgery as an independent risk factor of the PPS development (HR = 0.976; 95%CI: 0.956-0.996, p = 0.02). Cut-off point was established to assess the predictive value of IL-8 concentration (21.1 pg/ml). The test parameters were: sensitivity: 62.5%, specificity: 75%, positive predictive value: 83% and negative predictive value: 50%. Clinical evaluation showed the relationship between the hemoglobin concentration before the surgery and the PPS occurrence (p = 0.01). CONCLUSION: The IL-8 and IL-1β may participate in the postpericardiotomy syndrome pathogenesis, and the IL-8 concentration measurement may select patients with the risk of the PPS development. more...
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- 2014
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20. Supplementary Figures from IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
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Tomasz Skorski, Italo Tempera, Mariusz A. Wasik, Katarzyna Piwocka, Huaqing Zhao, Lena N. Lupey-Green, Margaret Nieborowska-Skorska, Daniel Gritsyuk, Michael Hulse, Yashodhara Dasgupta, Reza Nejati, Samantha K. Langer, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Kayla Martin, and Silvia Maifrede more...
- Abstract
Supplementary Figure S1. BL #1 cells display low HR activity. Supplementary Figure S2. BL #1 induced BL-like leukemia in NSG mice Supplementary Figure S3. IGH/MYC-positive cells are hypersensitive to RAD52 inhibitor. Supplementary Figure S4. IGH/MYC does not downregulate mRNA encoding BRCA2. Supplementary Figure S5. c-MYC regulates the expression of BRCA2 protein. Supplementary Figure S6. miR-1245 is upregulated in IGH/MYC-positive cells. more...
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- 2023
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21. Data from IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
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Tomasz Skorski, Italo Tempera, Mariusz A. Wasik, Katarzyna Piwocka, Huaqing Zhao, Lena N. Lupey-Green, Margaret Nieborowska-Skorska, Daniel Gritsyuk, Michael Hulse, Yashodhara Dasgupta, Reza Nejati, Samantha K. Langer, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Kayla Martin, and Silvia Maifrede more...
- Abstract
Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC–positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC–positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies.Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg.Mol Cancer Res; 15(8); 967–72. ©2017 AACR. more...
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- 2023
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22. Data from TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
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Tomasz Skorski, Grant A. Challen, Neil Johnson, Katarzyna Piwocka, Italo Tempera, George S. Vassiliou, Giovanni Martinelli, Jian Huang, Mark D. Minden, Mark R. Litzow, Hugo F. Fernandez, Martin S. Tallman, Elisabeth M. Paietta, Peter Valent, Stephen M. Sykes, Georg Greiner, Giorgia Simonetti, Daniela Di Marcantonio, Ksenia Matlawska-Wasowska, Boris A. Bartholdy, Kumaraswamy N. Chitrala, Antonella Padella, Zhaorui Lian, Zachary Gazze, Lisa Beatrice Caruso, Jozef Madzo, Kelsey Keith, Michael Hulse, Joseph Nacson, Wangisa M.B. Dunuwille, Katherine Sullivan-Reed, Konstantin Golovine, Margaret Nieborowska-Skorska, Bac Viet Le, and Silvia Maifrede more...
- Abstract
Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically.Significance:TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors. more...
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- 2023
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23. Supplementary Data from TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
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Tomasz Skorski, Grant A. Challen, Neil Johnson, Katarzyna Piwocka, Italo Tempera, George S. Vassiliou, Giovanni Martinelli, Jian Huang, Mark D. Minden, Mark R. Litzow, Hugo F. Fernandez, Martin S. Tallman, Elisabeth M. Paietta, Peter Valent, Stephen M. Sykes, Georg Greiner, Giorgia Simonetti, Daniela Di Marcantonio, Ksenia Matlawska-Wasowska, Boris A. Bartholdy, Kumaraswamy N. Chitrala, Antonella Padella, Zhaorui Lian, Zachary Gazze, Lisa Beatrice Caruso, Jozef Madzo, Kelsey Keith, Michael Hulse, Joseph Nacson, Wangisa M.B. Dunuwille, Katherine Sullivan-Reed, Konstantin Golovine, Margaret Nieborowska-Skorska, Bac Viet Le, and Silvia Maifrede more...
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Supplementary Methods and Results
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- 2023
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24. DNA Polymerase Theta Protects Leukemia Cells from Metabolic-Induced DNA Damage
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Umeshkumar M Vekariya, Katherine Sullivan-Reed, Monika Toma, Margaret Nieborowska-Skorska, Bac Viet Le, Marie-Christine Caron, Anna-Mariya Kukuyan, Paulina Podszywalow-Bartnicka, Kumaraswamy Chitrala, Jessica Atkins, Malgorzata Drzewiecka, Wanjuan Feng, Joe Chan, Konstantin Golovine, Jaroslav Jelinek, Tomasz Sliwinski, Jayashri Ghosh, Ksenia Maslawska-Wasowska, Reza Nejati, Mariusz A Wasik, Stephen M. Sykes, Katarzyna Piwocka, Emir Hadzijusufovic, Peter Valent, Richard Pomerantz, George Morton, Wayne Childers, Huaqing Zhao, Elisabeth Paietta, Ross L. Levine, Martin S. Tallman, Hugo F Fernandez, Mark R. Litzow, Gaorav P Gupta, Jean-Yves Masson, and Tomasz Skorski more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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25. Hypoxia, but Not Normoxia, Reduces Effects of Resveratrol on Cisplatin Treatment in A2780 Ovarian Cancer Cells: A Challenge for Resveratrol Use in Anticancer Adjuvant Cisplatin Therapy
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Agnieszka Synowiec, Klaudia Brodaczewska, Gabriel Wcisło, Aleksandra Majewska, Agata Borkowska, Aleksandra Filipiak-Duliban, Aleksandra Gawrylak, Kinga Wilkus, Katarzyna Piwocka, Agata Kominek, Halina Waś, Sławomir Lewicki, Jacek Siewiera, Cezary Szczylik, Jolanta Szenajch, Jacek Z. Kubiak, Claudine Kieda, Military Institute of Medicine, Warsaw, Centre of Postgraduate Medical Education [Warsaw, Poland] (CPME), Medical University of Warsaw - Poland, University of Warsaw (UW), Nencki Institute of Experimental Biology, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Ministry of Education and Sciences [425/2016], National Science Center grant [2016/23/B/NZ1/03211], European Social Fund, and Polish Ministry of National Defense [571/2016/DA, 508/2017/DA] more...
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ovarian cancer ,cisplatin ,resveratrol ,normoxia ,hypoxia ,epithelial–mesenchymal transition markers ,HIF-1α ,VEGF ,HIF-1 alpha ,Organic Chemistry ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,General Medicine ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,epithelial-mesenchymal transition markers - Abstract
International audience; Natural compounds, such as resveratrol (Res), are currently used as adjuvants for anticancer therapies. To evaluate the effectiveness of Res for the treatment of ovarian cancer (OC), we screened the response of various OC cell lines to the combined treatment with cisplatin (CisPt) and Res. We identified A2780 cells as the most synergistically responding, thus optimal for further analysis. Because hypoxia is the hallmark of the solid tumor microenvironment, we compared the effects of Res alone and in combination with CisPt in hypoxia (pO(2) = 1%) vs. normoxia (pO(2) = 19%). Hypoxia caused an increase (43.2 vs. 5.0%) in apoptosis and necrosis (14.2 vs. 2.5%), reactive oxygen species production, pro-angiogenic HIF-1a (hypoxia-inducible factor-1a) and VEGF (vascular endothelial growth factor), cell migration, and downregulated the expression of ZO1 (zonula occludens-1) protein in comparison to normoxia. Res was not cytotoxic under hypoxia in contrast to normoxia. In normoxia, Res alone or CisPt+Res caused apoptosis via caspase-3 cleavage and BAX, while in hypoxia, it reduced the accumulation of A2780 cells in the G2/M phase. CisPt+Res increased levels of vimentin under normoxia and upregulated SNAI1 expression under hypoxia. Thus, various effects of Res or CisPt+Res on A2780 cells observed in normoxia are eliminated or diminished in hypoxia. These findings indicate the limitations in using Res as an adjuvant with CisPt therapy in OC. more...
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- 2023
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26. Pre-Existing and Acquired Resistance to PARP Inhibitor-Induced Synthetic Lethality
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Bac Viet Le, Paulina Podszywałow-Bartnicka, Katarzyna Piwocka, and Tomasz Skorski
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Cancer Research ,Oncology - Abstract
The advanced development of synthetic lethality has opened the doors for specific anti-cancer medications of personalized medicine and efficient therapies against cancers. One of the most popular approaches being investigated is targeting DNA repair pathways as the implementation of the PARP inhibitor (PARPi) into individual or combinational therapeutic schemes. Such treatment has been effectively employed against homologous recombination-defective solid tumors as well as hematopoietic malignancies. However, the resistance to PARPi has been observed in both preclinical research and clinical treatment. Therefore, elucidating the mechanisms responsible for the resistance to PARPi is pivotal for the further success of this intervention. Apart from mechanisms of acquired resistance, the bone marrow microenvironment provides a pre-existing mechanism to induce the inefficiency of PARPi in leukemic cells. Here, we describe the pre-existing and acquired mechanisms of the resistance to PARPi-induced synthetic lethality. We also discuss the potential rationales for developing effective therapies to prevent/repress the PARPi resistance in cancer cells. more...
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- 2022
27. SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism
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Michal Mikula, Katarzyna Piwocka, Jolanta Wozniak, Ewa Jabłońska, Elżbieta Patkowska, Eliza Glodkowska-Mrowka, Patryk Górniak, Agnieszka Kolkowska-Lesniak, Przemyslaw Juszczynski, Natalia Baran, Marta Stojak, Karolina Piechna, Ewa Lech-Marańda, Beata Krzymieniewska, Lukasz Bugajski, Monika Noyszewska-Kania, Maciej Szydlowski, Anna Polak, Ewelina Kaniuga, Emilia Bialopiotrowicz, Magdalena Cybulska, and Joanna Barankiewicz more...
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Cancer Research ,Cell Respiration ,Immunology ,Syk ,Apoptosis ,Mice, SCID ,Fostamatinib ,Oxidative Phosphorylation ,Article ,Mice ,Cellular and Molecular Neuroscience ,Mice, Inbred NOD ,hemic and lymphatic diseases ,STAT5 Transcription Factor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Syk Kinase ,lcsh:QH573-671 ,Protein Kinase Inhibitors ,Oncogenesis ,STAT5 ,Cell Proliferation ,biology ,Gene Expression Regulation, Leukemic ,Cancer stem cells ,Kinase ,Chemistry ,lcsh:Cytology ,Tumor Suppressor Proteins ,Myeloid leukemia ,hemic and immune systems ,Cell Biology ,Translational research ,medicine.disease ,Xenograft Model Antitumor Assays ,Leukemia, Myeloid, Acute ,Oxidative Stress ,Leukemia ,Mitochondrial biogenesis ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,Female ,Stem cell ,medicine.drug - Abstract
Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38−CD123+ and CD34+CD38−CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials. more...
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- 2020
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28. Abstract 2642: Nascent proteome of leukemia cells in the hypoxic bone marrow microenvironment – role of TIAR and FMRP
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Paulina Podszywalow-Bartnicka, Magdalena Wolczyk, Remigiusz Serwa, Laura Turos-Korgul, Jacek Milek, Marta Chwalek, Michal Dabrowski, Magdalena Dziembowska, and Katarzyna Piwocka
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Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
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29. Chronic myeloid leukemia‐derived extracellular vesicles increase Foxp3 level and suppressive activity of thymic regulatory T cells
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Ewa Kozlowska, Wioleta Dudka, Marta Brewińska-Olchowik, Katarzyna Piwocka, Lukasz Bugajski, and Julian Swatler
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0301 basic medicine ,Blast Crisis ,medicine.medical_treatment ,Immunology ,Thymus Gland ,Biology ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Extracellular vesicles ,regulatory T cells ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,chronic myeloid leukemia ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Immune Tolerance ,medicine ,Humans ,Immunology and Allergy ,Letter to the Editor ,Transcription factor ,Cells, Cultured ,immunosuppression ,Gene Expression Regulation, Leukemic ,FOXP3 ,Myeloid leukemia ,Forkhead Transcription Factors ,Immunosuppression ,Up-Regulation ,030104 developmental biology ,medicine.anatomical_structure ,Foxp3 ,Neoplastic Stem Cells ,Cancer research ,Bone marrow ,Function (biology) ,030215 immunology - Abstract
Mechanisms driving immunosuppression in chronic myeloid leukemia are mostly unknown. We show that leukemic extracellular vesicles (EVs) target lymphocytes and amplify suppressive function of thymic regulatory T cells, by driving expression of Foxp3 transcription factor. This could facilitate expansion of leukemic cells outside the bone marrow, leading to blast crisis. more...
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- 2019
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30. Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells
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Wioleta Dudka, Katja Srpan, Daniel M. Davis, Monika Zaręba-Kozioł, Jakub Wlodarczyk, Agata Klejman, Yannick Schwab, Agata Kominek, Katarzyna Piwocka, Paolo Ronchi, Dominik Cysewski, Laura Turos, Piotr Chroscicki, and Marta D. Kolba more...
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Cancer microenvironment ,Cancer Research ,Stromal cell ,medicine.drug_class ,Immunology ,Cell Communication ,Tyrosine-kinase inhibitor ,Article ,Cellular and Molecular Neuroscience ,Stroma ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,lcsh:QH573-671 ,Nanotubes ,Chemistry ,lcsh:Cytology ,Vesicle ,Myeloid leukemia ,Biological Transport ,Cell Biology ,medicine.disease ,Cell biology ,Mitochondria ,Leukemia ,Microscopy, Electron ,medicine.anatomical_structure ,Mechanisms of disease ,Cell culture ,Drug Resistance, Neoplasm ,Imatinib Mesylate ,Bone marrow ,Stromal Cells ,Haematological diseases - Abstract
Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor–ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs)—long, thin membranous structures, which have been identified as a novel mode of intercellular cross-talk—are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity with the cell bodies and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stromal to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells. more...
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- 2019
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31. Identification of Multi-Omics Cell Signatures of Early Liver Injury
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Katarzyna Kedzierska, Maciej Migdal, Michał Pawlak, Cecilia Lanny Winata, Łukasz Bugajski, Katarzyna Piwocka, Eugeniusz Tralle, Karim Abu Nahia, and Filip Garbicz
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Liver injury ,medicine.anatomical_structure ,Cell ,medicine ,Multi omics ,Identification (biology) ,Computational biology ,Biology ,medicine.disease - Abstract
Background Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Results In this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype. Conclusion Our results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals. more...
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- 2021
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32. TET2 and DNMT3A Mutations Exert Divergent Effects on DNA Repair and Sensitivity of Leukemia Cells to PARP Inhibitors
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Margaret Nieborowska-Skorska, Kumaraswamy Naidu Chitrala, Joseph Nacson, Daniela Di Marcantonio, Georg Greiner, Mark R. Litzow, Neil Johnson, George S. Vassiliou, Martin S. Tallman, Grant A. Challen, Kelsey Keith, Antonella Padella, Giovanni Martinelli, Lisa Beatrice Caruso, Elisabeth Paietta, Tomasz Skorski, Konstantin Golovine, Jian Huang, Jozef Madzo, Giorgia Simonetti, Silvia Maifrede, Ksenia Matlawska-Wasowska, Bac Viet Le, Katherine Sullivan-Reed, Katarzyna Piwocka, Peter Valent, Mark D. Minden, Michael Hulse, Hugo F. Fernandez, Stephen M. Sykes, Zachary Gazze, Italo Tempera, Wangisa M.B. Dunuwille, Boris Bartholdy, and Zhaorui Lian more...
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Cancer Research ,Mutation ,DNA repair ,Dioxygenase activity ,Synthetic lethality ,Biology ,medicine.disease_cause ,Article ,PARP1 ,Oncology ,PARP inhibitor ,DNA methylation ,embryonic structures ,Cancer research ,medicine ,Epigenetics - Abstract
Somatic variants in TET2 and DNMT3A are founding mutations in hematological malignancies that affect the epigenetic regulation of DNA methylation. Mutations in both genes often co-occur with activating mutations in genes encoding oncogenic tyrosine kinases such as FLT3ITD, BCR-ABL1, JAK2V617F, and MPLW515L, or with mutations affecting related signaling pathways such as NRASG12D and CALRdel52. Here, we show that TET2 and DNMT3A mutations exert divergent roles in regulating DNA repair activities in leukemia cells expressing these oncogenes. Malignant TET2-deficient cells displayed downregulation of BRCA1 and LIG4, resulting in reduced activity of BRCA1/2-mediated homologous recombination (HR) and DNA-PK–mediated non-homologous end-joining (D-NHEJ), respectively. TET2-deficient cells relied on PARP1-mediated alternative NHEJ (Alt-NHEJ) for protection from the toxic effects of spontaneous and drug-induced DNA double-strand breaks. Conversely, DNMT3A-deficient cells favored HR/D-NHEJ owing to downregulation of PARP1 and reduction of Alt-NHEJ. Consequently, malignant TET2-deficient cells were sensitive to PARP inhibitor (PARPi) treatment in vitro and in vivo, whereas DNMT3A-deficient cells were resistant. Disruption of TET2 dioxygenase activity or TET2—Wilms' tumor 1 (WT1)–binding ability was responsible for DNA repair defects and sensitivity to PARPi associated with TET2 deficiency. Moreover, mutation or deletion of WT1 mimicked the effect of TET2 mutation on DSB repair activity and sensitivity to PARPi. Collectively, these findings reveal that TET2 and WT1 mutations may serve as biomarkers of synthetic lethality triggered by PARPi, which should be explored therapeutically. Significance: TET2 and DNMT3A mutations affect distinct DNA repair mechanisms and govern the differential sensitivities of oncogenic tyrosine kinase–positive malignant hematopoietic cells to PARP inhibitors. more...
- Published
- 2021
33. Targeting Integrated Stress Response by ISRIB combined with imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells
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Magdalena Wolczyk, Marta Brewińska-Olchowik, Katarzyna Piwocka, Julian Swatler, Ilona Seferynska, Shamba S Mondal, Monika Kusio-Kobialka, Agata Klejman, Laura Turos-Korgul, Wioleta Dudka, Milena Wiech, Marcin M Machnicki, Agata Kominek, Tomasz Stoklosa, and Grazyna Hoser more...
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MAPK/ERK pathway ,biology ,business.industry ,Myeloid leukemia ,Imatinib ,medicine.disease ,ISRIB ,Dasatinib ,Leukemia ,hemic and lymphatic diseases ,Cancer research ,biology.protein ,Medicine ,Integrated stress response ,business ,STAT5 ,medicine.drug - Abstract
Integrated Stress Response (ISR) facilitates cellular adaptation to variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CM Blast Crisis (BC) D34+ resistant cells. We found that in Patient Derived Xenograft (PDX) mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFNγ pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation. more...
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- 2021
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34. IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen
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Magdalena Zawada, Jerzy Holowiecki, Magdalena Wojtas, Sebastian Giebel, Agnieszka Przybylowicz, Anna Ejduk, I. Florek, Agnieszka Wierzbowska, Dariusz Kata, Kazimierz Kuliczkowski, Tomasz Wróbel, Beata Piatkowska-Jakubas, Przemysław Juszczynski, Marta Libura, Katarzyna Piwocka, Sylwia Czekalska, Marzena Wojtaszewska, Emilia Bialopiotrowicz, Karolina Matiakowska, Iwona Solarska, Tomasz Sacha, Patryk Gorniak, Tadeusz Robak, Elżbieta Urbanowska, Gail J. Roboz, Wiesław Wiktor Jędrzejczak, Agnieszka Sroka-Porada, Agnieszka Pluta, Wanda Knopinska, Justyna Gajkowska-Kulik, Krzysztof Warzocha, Anna Wróbel, Monika Paluszewska, Sebastian Grosicki, Karolina Karabin, Marta Pawelczyk, Bozena Jazwiec, Katarzyna Borg, Justyna Rybka, Grzegorz W. Basak, Olga Haus, Lidia Gil, Lukasz Bolkun, Agata Kominek, Grazyna Semenczuk, Agnieszka Piekarska, Krzysztof Lewandowski, Zoriana Salamanczuk, Karolina Pyziak, Katarzyna Wasilewska, Karolina Piechna, and Monika Noyszewska-Kania more...
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Adult ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,IDH1 ,Adolescent ,Pharmacogenomic Variants ,Daunorubicin ,medicine.medical_treatment ,Science ,Population ,Antineoplastic Agents ,IDH2 ,Article ,Acute myeloid leukaemia ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cancer epigenetics ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Chemotherapy ,Cladribine ,education ,Aged ,Randomized Controlled Trials as Topic ,Retrospective Studies ,education.field_of_study ,Multidisciplinary ,business.industry ,Cytarabine ,Middle Aged ,Isocitrate Dehydrogenase ,Leukemia, Myeloid, Acute ,Regimen ,030104 developmental biology ,030220 oncology & carcinogenesis ,Medicine ,Poland ,business ,medicine.drug - Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients’ outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37–0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant. more...
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- 2021
35. Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia
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Paulina Podszywalow-Bartnicka, Katarzyna Piwocka, and Magdalena Wolczyk
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0301 basic medicine ,Acute leukemia ,business.industry ,InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,Treatment strategy ,Medicine ,business ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Post-transcriptional regulation - Abstract
Post-transcriptional regulation is an important step of gene expression that allows to fine-tune the cellular protein profile (so called proteome) according to the current demands. That mechanism has been developed to aid survival under stress conditions, however it occurs to be hijacked by cancer cells. Adjustment of the protein profile remodels signaling in cancer cells to adapt to therapeutic treatment, thereby enabling persistence despite unfavorable environment or accumulating mutations. The proteome is shaped at the post-transcriptional level by numerous mechanisms such as alternative splicing, mRNA modifications and triage by RNA binding proteins, change of ribosome composition or signaling, which altogether regulate the translation process. This chapter is an overview of the translation disturbances found in leukemia and their role in development of the disease, with special focus on the possible therapeutic strategies tested in acute leukemia which target elements of those regulatory mechanisms. more...
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- 2021
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36. Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias
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Julian Swatler, Katarzyna Piwocka, Laura Turos-Korgul, and Ewa Kozlowska
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0301 basic medicine ,Cancer Research ,Myeloid ,medicine.medical_treatment ,Review ,acute myeloid leukemia ,myeloid derived suppressor cells ,lcsh:RC254-282 ,regulatory T cells ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,chronic myeloid leukemia ,hemic and lymphatic diseases ,medicine ,Cytotoxic T cell ,immunosuppression ,business.industry ,Myeloid leukemia ,Immunosuppression ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,medicine.anatomical_structure ,inhibitory receptors ,Oncology ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,Cancer research ,Bone marrow ,business ,extracellular vesicles ,CD8 - Abstract
Simple Summary Effector immune system cells have the ability to kill tumor cells. However, as a cancer (such as leukemia) develops, it inhibits and evades the effector immune response. Such a state of immunosuppression can be driven by several factors – receptors, soluble cytokines, as well as by suppressive immune cells. In this review, we describe factors and cells that constitute immunosuppressive microenvironment of myeloid leukemias. We characterize factors of direct leukemic origin, such as inhibitory receptors, enzymes and extracellular vesicles. Furthermore, we describe suppressive immune cells, such as myeloid derived suppressor cells and regulatory T cells. Finally, we sum up changes in these drivers of immune evasion in myeloid leukemias during therapy. Abstract Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy. more...
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- 2021
37. Transcriptome profile of the sinoatrial ring reveals conserved and novel genetic programs of the zebrafish pacemaker
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Hans Binder, Karim Abu Nahia, Katarzyna Piwocka, Alexandra Paterek, Cecilia Lanny Winata, Shikha Vashisht, Vladimir Korzh, Angelika Brzozowska, Henry Loeffler-Wirth, Yusra H Siddiqui, Lukasz Bugajski, Tomasz Obrębski, and Rashid Minhas more...
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Sequencing data ,European Regional Development Fund ,Library science ,QH426-470 ,Biology ,Sinoatrial node ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Genetics ,media_common.cataloged_instance ,Animals ,Humans ,European union ,Cardiac conduction system ,Zebrafish ,030304 developmental biology ,media_common ,0303 health sciences ,fungi ,030302 biochemistry & molecular biology ,Opus ,Pacemaker ,Sinoatrial ring ,RNA-seq ,Transcriptome ,TP248.13-248.65 ,030217 neurology & neurosurgery ,Biotechnology ,Research Article - Abstract
Background Sinoatrial Node (SAN) is part of the cardiac conduction system, which controls the rhythmic contraction of the vertebrate heart. The SAN consists of a specialized pacemaker cell population that has the potential to generate electrical impulses. Although the SAN pacemaker has been extensively studied in mammalian and teleost models, including the zebrafish, their molecular nature remains inadequately comprehended. Results To characterize the molecular profile of the zebrafish sinoatrial ring (SAR) and elucidate the mechanism of pacemaker function, we utilized the transgenic line sqet33mi59BEt to isolate cells of the SAR of developing zebrafish embryos and profiled their transcriptome. Our analyses identified novel candidate genes and well-known conserved signaling pathways involved in pacemaker development. We show that, compared to the rest of the heart, the zebrafish SAR overexpresses several mammalian SAN pacemaker signature genes, which include hcn4 as well as those encoding calcium- and potassium-gated channels. Moreover, genes encoding components of the BMP and Wnt signaling pathways, as well as members of the Tbx family, which have previously been implicated in pacemaker development, were also overexpressed in the SAR. Among SAR-overexpressed genes, 24 had human homologues implicated in 104 different ClinVar phenotype entries related to various forms of congenital heart diseases, which suggest the relevance of our transcriptomics resource to studying human heart conditions. Finally, functional analyses of three SAR-overexpressed genes, pard6a, prom2, and atp1a1a.2, uncovered their novel role in heart development and physiology. Conclusion Our results established conserved aspects between zebrafish and mammalian pacemaker function and revealed novel factors implicated in maintaining cardiac rhythm. The transcriptome data generated in this study represents a unique and valuable resource for the study of pacemaker function and associated heart diseases. more...
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- 2020
38. Author response: Splicing variation of BMP2K balances abundance of COPII assemblies and autophagic degradation in erythroid cells
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Marta Brewińska-Olchowik, Jaroslaw Cendrowski, Katarzyna Piwocka, Katarzyna Kuzmicz-Kowalska, Kamil Jastrzębski, Agata Kominek, Marta Kaczmarek, Michał Mazur, and Marta Miaczynska
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Variation (linguistics) ,Chemistry ,Abundance (ecology) ,RNA splicing ,Autophagy ,Degradation (geology) ,COPII ,Cell biology - Published
- 2020
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39. Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses
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Marta Brewińska-Olchowik, Blair Stewig, Krzysztof Kolmus, Katarzyna Piwocka, Purevsuren Erdenebat, Ewelina Szymańska, Edyta Derezińska-Wołek, Marta Miączyńska, Krzysztof Goryca, Michal Mikula, Monika Prochorec-Sobieszek, and Anna Szumera-Ciećkiewicz more...
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0301 basic medicine ,Gene knockdown ,Endosomal Sorting Complexes Required for Transport ,Chemistry ,Cell growth ,Cell Biology ,Biology ,Endocytosis ,medicine.disease_cause ,ESCRT ,Cell biology ,Transcriptome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,TSG101 ,Humans ,Protein kinase A ,Carcinogenesis ,Transcription factor ,Transcription Factors - Abstract
Molecular details of how endocytosis contributes to oncogenesis remain elusive. Our in silico analysis of colorectal cancer (CRC) patients revealed stage-dependent alterations in the expression of 113 endocytosis-related genes. Among them transcription of the Endosomal Sorting Complex Required for Transport (ESCRT)-I component VPS37B was decreased in the advanced stages of CRC. Expression of other ESCRT-I core subunits remained unchanged in the investigated dataset. We analyzed an independent cohort of CRC patients showing also reduced VPS37A mRNA and protein abundance. Transcriptomic profiling of CRC cells revealed non-redundant functions of Vps37 proteins. Knockdown of VPS37A and VPS37B triggered p21-mediated inhibition of cell proliferation and sterile inflammatory response driven by the Nuclear Factor (NF)-κB transcription factor and associated with mitogen-activated protein kinase signaling. Co-silencing of VPS37C further potentiated activation of these independently induced processes. The type and magnitude of transcriptional alterations correlated with the differential ESCRT-I stability upon individual and concurrent Vps37 depletion. Our study provides novel insights into cancer cell biology by describing cellular stress responses that are associated with ESCRT-I destabilization, which might occur in CRC patients.SUMMARY STATEMENTEndosomal Sorting Complex Required for Transport (ESCRT)-I destabilization upon concurrent depletion of Vps37 proteins is linked to the activation of sterile inflammatory response and cell growth inhibition. more...
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- 2020
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40. Isolation and Characterization of Extracellular Vesicles from Cell Culture Conditioned Medium for Immunological Studies
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Katarzyna Piwocka, Wioleta Dudka, and Julian Swatler
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Immunoassay ,0301 basic medicine ,Differential centrifugation ,Chemistry ,Immunology ,Nanoparticle tracking analysis ,General Medicine ,Extracellular vesicle ,Lymphocyte Subsets ,In vitro ,Cell biology ,Blot ,Extracellular Vesicles ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Cell culture ,Culture Media, Conditioned ,Humans ,Lymphocytes ,Ultracentrifugation ,Cells, Cultured ,Intracellular ,030215 immunology - Abstract
Extracellular vesicles (EVs) are small, membranous particles that have recently emerged as one the most important mediators of intercellular communication. They can contain a variety of proteins, lipids, and nucleic acids and thus are responsible for modulation of multiple biological processes, including immune response and regulation of immune cells. Immunomodulatory activity of different EVs can be reliably assessed using EVs isolated from cell culture conditioned medium and added to in vitro or ex vivo cultures of immune cells. This article describes protocols for isolation of EVs from cell culture supernatants by differential ultracentrifugation and density gradient centrifugation. It also provides tools and protocols that enable characterization and validation of isolated particles, as well as analysis of interactions between EVs of interest and different subpopulations of human immune cells. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Isolation of extracellular vesicles by differential ultracentrifugation Basic Protocol 2: Isolation of extracellular vesicles by density gradient centrifugation Support Protocol 1: Imaging of extracellular vesicles using transmission electron microscopy Support Protocol 2: Detection of extracellular vesicle protein markers by Western blotting Support Protocol 3: Measurement and counting of extracellular vesicles by nanoparticle tracking analysis Basic Protocol 3: Analysis of extracellular vesicle uptake or association by different subpopulations of lymphocytes in vitro. more...
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- 2020
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41. Splicing variation of BMP2K balances endocytosis, COPII trafficking and autophagy in erythroid cells
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Marta Miaczynska, Katarzyna Piwocka, Agata Kominek, Michał Mazur, Jaroslaw Cendrowski, Marta Brewińska-Olchowik, Marta Kaczmarek, Kamil Jastrzębski, and Katarzyna Kuzmicz-Kowalska
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Chemistry ,Kinase ,Cellular differentiation ,Autophagy ,Bone morphogenetic protein ,Endocytosis ,COPII ,Intracellular ,K562 cells ,Cell biology - Abstract
Intracellular transport undergoes remodeling upon cell differentiation, which involves cell type-specific regulators. Bone morphogenetic protein 2-inducible kinase (BMP2K) has been potentially implicated in endocytosis and cell differentiation but its molecular functions remained unknown. We discovered that its longer (L) and shorter (S) splicing variants regulate erythroid differentiation in a manner unexplainable by their involvement in AP-2 adaptor phosphorylation and endocytosis. However, both variants interacted with SEC16A whose silencing in K562 erythroid leukemia cells affected generation of COPII assemblies and induced autophagic degradation. Variant-specific depletion approach showed that BMP2K isoforms constitute a BMP2K-L/S regulatory system. Therein, L promotes while S restricts recruitment of SEC31A to SEC24B-containing COPII structures forming at SEC16A-positive ER exit sites. Finally, we found L to promote and S to restrict autophagic degradation. Hence, we propose that BMP2K-L favors SEC16A-dependent intracellular processes important for erythroid maturation, such as COPII trafficking and autophagy, in a manner inhibited by BMP2K-S. more...
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- 2020
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42. TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment
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Tomasz Skorski, Katarzyna Piwocka, Peter Valent, Juo-Chin Yao, Margaret Nieborowska-Skorska, Martin S. Tallman, Mark R. Litzow, Jian Huang, Paulina Podszywalow-Bartnicka, Zhaorui Lian, Konstantin Golovine, Julian Swatler, Elisabeth Paietta, Silvia Maifrede, Italo Tempera, Michal Dabrowski, Lisa Beatrice Caruso, Kathy Q. Cai, Daniel C. Link, Bac Viet Le, Grant A. Challen, Ross L. Levine, Reza Nejati, Hugo F. Fernandez, Katherine Sullivan-Reed, and Mariusz A. Wasik more...
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0301 basic medicine ,Stromal cell ,Synthetic lethality ,Poly(ADP-ribose) Polymerase Inhibitors ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,PARP1 ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Smad3 Protein ,lcsh:QH301-705.5 ,TGFβR signaling ,bone marrow microenvironment ,biology ,Chemistry ,Kinase ,Transforming growth factor beta ,medicine.disease ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,PARP inhibitor ,Cancer research ,biology.protein ,PARP inhibitor resistance ,Bone marrow ,Receptors, Transforming Growth Factor beta ,030217 neurology & neurosurgery - Abstract
Summary: Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis. more...
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- 2020
43. Deficyty BRCA1 i syntetyczna letalność w białaczkach; nie tylko mutacje mają znaczenie
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Katarzyna Piwocka, Paulina Podszywalow-Bartnicka, and Tomasz Skorski
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PARP1 ,DNA repair ,Cancer cell ,Cancer research ,General Medicine ,Synthetic lethality ,Epigenetics ,Gene mutation ,Biology ,Homologous recombination ,Synthetic Lethal Mutations - Abstract
BRCA1 jest jednym z głównych regulatorów stabilności genomowej w komórce. Odpowiada ze kontrolę segregacji chromosomów oraz komórek potomnych po podziale oraz reguluje naprawę dwuniciowych pęknęć DNA poprzez rekombinację homologiczną (HR). Zmiany genetyczne na poziomie genu BRCA1, takie jak mutacje i zmiany epigenetyczne są markerem predyspozycji w kierunku zachorowania na nowotwór piersi, jajnika i prostaty, istotnie zwiększając ryzyko wystąpienia nowotworu. Zmiany takie nie są obserwowane w białaczkach. Co ważne, deficyty BRCA1 są czynnikiem wskazującym na wrażliwość pacjentów na personalizowaną terapię inhibitorami PARP1, opartą o zjawisko tzw. syntetycznej letalności. W niniejszej pracy przedstawiamy nasze badania prowadzące do odkrycia nowego mechanizmu prowadzącego do deficytów BRCA1 w białaczkach, który nie jest związany z mutacjami lub innymi zmianami na poziomie genu, lecz z zahamowaną translacją i deficytem białka BRCA1. Zaburzenia te są efektem aktywacji komórkowej odpowiedzi na stres i kontrolowane przez białka wiążące RNA. Co więcej, wykazaliśmy, że pewne terapie jak i zmiany genetyczne w białaczkach także mogą wywołać deficyty BRCA1. Nasze badania dowiodły, że inhibitory PARP1 powinny być rozważane jako skuteczne terapeutyki w przypadku białaczek z niedoborem BRCA1, prowadząc do skutecznej eliminacji komórek nowotworu, w tym także komórek macierzystych i progenitorowych. W końcu, w wyniku naszych badań, zaproponowaliśmy strategię selekcji pacjentów z białaczkami, którzy będą wrażliwi na terapię inhibitorami PARP1. more...
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- 2018
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44. Characteristics of live parameters of the HS-5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia-stroma cross-talk
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Paulina Podszywalow-Bartnicka, Katarzyna Piwocka, Magdalena Wolczyk, Julian Swatler, Agata Kominek, and Marta D. Kolba
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0301 basic medicine ,Cell type ,Histology ,Stromal cell ,medicine.diagnostic_test ,Cell ,Cell Biology ,Biology ,medicine.disease ,Pathology and Forensic Medicine ,Flow cytometry ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,Apoptosis ,medicine ,Cancer research ,Bone marrow - Abstract
The unique bone marrow microenvironment is created by stromal cells and such physical conditions as hypoxia. Both hypoxia and interactions with stromal cells have a significant impact on the biology of leukemia cells, changing their sensitivity to antileukemic therapies. Thus, it is crucial to introduce biological systems, which enable the investigation of leukemia-stroma cross-talk and verification of novel therapies effectiveness under such bone marrow niche-mimicking conditions. Here, we have established an experimental setup based on the hypoxic co-culture of stromal cells with different cell lines derived from various leukemia patients. Flow cytometry enables simultaneous fluorescent tracking of viable cells and analysis of fundamental cellular processes, also to monitor the basal vital state of cells in the hypoxic co-culture. This is critically important, as the stromal cells deliver a big variability of signals to protect leukemia cells and provide drug resistance. Therefore, keeping stromal cells at the healthy state is crucial during experimental procedures. In the proposed studies, viability, apoptosis, proliferation, ROS production, and mitochondrial membrane potential were monitored in both cell types, which were separated on the basis of the fluorescence of a cell tracker. We have shown that the proposed hypoxic co-culture conditions do not affect basal live parameters of stromal cells, indicating the relevance of proposed model. Finally, we utilized this experimental setup to monitor the stroma-mediated protection of leukemia cells from the imatinib-induced cell death, which contributes to the leukemia progression and development of therapy resistance. Altogether, we recommend such flow cytometric strategy as an elementary screen of the vital state of stromal cells, which should be performed when using the co-culture hypoxic models. The proposed approach can also be broadly used for other studies of the leukemia-stroma cross-talk and of the part played by the leukemic microenvironment in drug screening studies. more...
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- 2018
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45. Transcriptome profile of the zebrafish atrioventricular canal reveals molecular signatures of pacemaker and valve mesenchyme
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Karim, Abu Nahia, primary, Maciej, Migdał, additional, Alexander, Quinn T., additional, Kar-Lai, Poon, additional, Maciej, Łapinski, additional, Agata, Sulej, additional, Michał, Pawlak, additional, Łukasz, Bugajski, additional, Katarzyna, Piwocka, additional, Thomas, Brand, additional, Peter, Kohl, additional, Vladimir, Korzh, additional, and Cecilia, Winata, additional more...
- Published
- 2021
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46. Transient MicroRNA Expression Enhances Myogenic Potential of Mouse Embryonic Stem Cells
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Maria A. Ciemerych, Katarzyna Piwocka, Iwona Grabowska, Joanna Bem, Anna Fogtman, Lukasz Bugajski, Dorota Zawada, Areta M. Czerwinska, and Maciej Daniszewski
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0301 basic medicine ,Cellular differentiation ,PAX3 ,Embryoid body ,Biology ,Muscle Development ,Myoblasts ,Mice ,03 medical and health sciences ,Animals ,Progenitor cell ,Cells, Cultured ,Embryoid Bodies ,Embryonic Stem Cells ,reproductive and urinary physiology ,Myogenesis ,Cell Differentiation ,Cell Biology ,Embryonic stem cell ,Cell biology ,MicroRNAs ,030104 developmental biology ,embryonic structures ,Molecular Medicine ,MYF5 ,biological phenomena, cell phenomena, and immunity ,Stem cell ,Developmental Biology - Abstract
MicroRNAs (miRNAs) are known regulators of various cellular processes, including pluripotency and differentiation of embryonic stem cells (ESCs). We analyzed differentiation of two ESC lines—D3 and B8, and observed significant differences in the expression of miRNAs and genes involved in pluripotency and differentiation. We also examined if transient miRNA overexpression could serve as a sufficient impulse modulating differentiation of mouse ESCs. ESCs were transfected with miRNA Mimics and differentiated in embryoid bodies and embryoid body outgrowths. miRNAs involved in differentiation of mesodermal lineages, such as miR145 and miR181, as well as miRNAs regulating myogenesis (MyomiRs)—miR1, miR133a, miR133b, and miR206 were tested. Using such approach, we proved that transient overexpression of molecules selected by us modulated differentiation of mouse ESCs. Increase in miR145 levels upregulated Pax3, Pax7, Myod1, Myog, and MyHC2, while miR181 triggered the expression of such crucial myogenic factors as Myf5 and MyHC2. As a result, the ability of ESCs to initiate myogenic differentiation and form myotubes was enhanced. Premature expression of MyomiRs had, however, an adverse effect on myogenic differentiation of ESCs. more...
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- 2018
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47. P16.09 Regulation of chromatin accessibility in the hypoxic tumor microenvironment of glioblastoma
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Katarzyna Piwocka, M Dzwigonska, Agata Kominek, Bozena Kaminska, Paulina Pilanc, Katarzyna B. Leszczynska, Jakub Mieczkowski, and Salwador Cyranowski
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Cancer Research ,Tumor microenvironment ,Tumor hypoxia ,Microglia ,medicine.medical_treatment ,Cancer ,Biology ,medicine.disease ,Chromatin ,Poster Presentations ,Cytokine ,medicine.anatomical_structure ,Oncology ,Glioma ,Gene expression ,medicine ,Cancer research ,Neurology (clinical) - Abstract
BACKGROUND Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most aggressive type of primary brain tumor. GBM has the poorest prognosis with no efficient cure to date due to diffusive growth into the brain, resistance to treatments and the immunosuppressive tumor microenvironment (TME). The growth and invasiveness of GBM is supported by the heterogeneous TME including local microglia and bone-marrow-derived macrophages (collectively known as glioma-associated microglia and macrophages, GAMs). In addition, tumor hypoxia is a key factor in the progression of GBM, as it can globally and rapidly alter gene expression, induce cancer cell invasiveness, stemness and lead to therapy resistance. Hypoxia can influence the pro-tumorigenic function of GAMs by inducing the expression of cytokines and cell surface receptors. However, little is known on the hypoxia-imposed chromatin changes of GAMs and GBM cells, which can in turn impact the interaction between these cell populations. Here we analyze these changes using a single-cell method, which preserves in situ hypoxia within the TME of GBM. MATERIAL AND METHODS Single-cell Pi-ATAC-seq (Protein-indexed Assay of Transposase Accessible Chromatin with sequencing) method in a GL261 murine glioma model was used to simultaneously assess genome-wide chromatin accessibility and expression of intracellular protein markers in single cells, enabling accurate selection of hypoxic and non-hypoxic tumor cells and GAMs. Pi-ATAC-seq is used on paraformaldehyde-perfused tumors and therefore allows capturing unaltered hypoxia-dependent cellular states, that often become distorted during dissociation and preparation of fresh material in most common single-cell methods. RESULTS We optimized Pi-ATAC method in a GL261 GBM mouse model, with specific sorting of GAMs using CD11b+ immunosorting followed by separation of microglia and macrophages, based on intensity of CD45 staining. HIF-1α induction and binding of pimonidazole were used to mark hypoxic populations. Currently, we are investigating the chromatin accessibility profiles of cancer cells and GAMs within the hypoxic tumor microenvironment of GBM. Exploring open chromatin profiles in GAMs and glioma-microglia co-cultures will allow to unravel the mechanisms of chromatin accessibility modulation in the oxygen-dependent manner. CONCLUSION In summary, we optimized the Pi-ATAC method in a mouse GBM model to characterize the chromatin openness changes in GAMs and cancer cells in response to hypoxic stress. Further validation of these results will provide the potential to identify novel markers for GAMs/glioma interactions in hypoxic GBMs and develop novel therapeutic targets. more...
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- 2021
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48. IGH/MYC Translocation Associates with BRCA2 Deficiency and Synthetic Lethality to PARP1 Inhibitors
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Lena N Lupey-Green, Yashodhara Dasgupta, Katarzyna Piwocka, Italo Tempera, Michael Hulse, Katherine Sullivan-Reed, Paulina Podszywalow-Bartnicka, Margaret Nieborowska-Skorska, Reza Nejati, Samantha Langer, Mariusz A. Wasik, Huaqing Zhao, Silvia Maifrede, Daniel Gritsyuk, Tomasz Skorski, and Kayla A. Martin more...
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0301 basic medicine ,Cancer Research ,DNA Repair ,Genes, myc ,Poly (ADP-Ribose) Polymerase-1 ,Chromosomal translocation ,Synthetic lethality ,Biology ,Piperazines ,Translocation, Genetic ,Article ,Olaparib ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,PARP1 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,DNA Breaks, Double-Stranded ,Homologous Recombination ,Molecular Biology ,BRCA2 Protein ,Oncogene ,Cytarabine ,medicine.disease ,Burkitt Lymphoma ,Xenograft Model Antitumor Assays ,3. Good health ,Lymphoma ,Leukemia ,030104 developmental biology ,Oncology ,chemistry ,Cancer research ,Phthalazines ,Synthetic Lethal Mutations ,medicine.drug - Abstract
Burkitt lymphoma/leukemia cells carry t(8;14)(q24;q32) chromosomal translocation encoding IGH/MYC, which results in the constitutive expression of the MYC oncogene. Here, it is demonstrated that untreated and cytarabine (AraC)-treated IGH/MYC–positive Burkitt lymphoma cells accumulate a high number of potentially lethal DNA double-strand breaks (DSB) and display low levels of the BRCA2 tumor suppressor protein, which is a key element of homologous recombination (HR)-mediated DSB repair. BRCA2 deficiency in IGH/MYC–positive cells was associated with diminished HR activity and hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary Burkitt lymphoma xenografts. In conclusion, IGH/MYC–positive Burkitt lymphoma/leukemia cells have decreased BRCA2 and are sensitive to PARP1 inhibition alone or in combination with other chemotherapies. Implications: This study postulates that IGH/MYC–induced BRCA2 deficiency may predispose Burkitt lymphoma cells to synthetic lethality triggered by PARP1 inhibitors. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/8/967/F1.large.jpg. Mol Cancer Res; 15(8); 967–72. ©2017 AACR. more...
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- 2017
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49. Corrigendum: Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development
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Cecilia Lanny Winata, Katarzyna Kedzierska, Piero Carninci, Katarzyna Piwocka, Lukasz Bugajski, Karim Abu Nahia, Michał Pawlak, Jordan A. Ramilowski, Maciej Migdal, Kosuke Hashimoto, and Aleksandra Marconi more...
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Transcriptome ,Heart development ,Genetics ,Key (cryptography) ,Computational biology ,Biology ,Corrigenda ,Genetics (clinical) ,Chromatin - Published
- 2020
50. Erratum for the Research Article: 'ESCRT proteins restrict constitutive NF-κB signaling by trafficking cytokine receptors' by A. Mamińska, A. Bartosik, M. Banach-Orłowska, I. Pilecka, K. Jastrzębski, D. Zdżalik-Bielecka, I. Castanon, M. Poulain, C. Neyen, L. Wolińska-Nizioł, A. Toruń, E. Szymańska, A. Kowalczyk, K. Piwocka, A. Simonsen, H. Stenmark, M. Fürthauer, M. González-Gaitán, M. Miaczynska
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Iwona Pilecka, Magdalena Banach-Orlowska, Claudine Neyen, Anne Simonsen, Harald Stenmark, Daria Zdżalik-Bielecka, Anna Torun, Ewelina Szymańska, Kamil Jastrzębski, Lidia Wolińska-Nizioł, Agnieszka Mamińska, Katarzyna Piwocka, Maximilian Fürthauer, Irinka Castanon, Morgane Poulain, Anna Bartosik, Agata Kowalczyk, Marcos González-Gaitán, and Marta Miaczynska more...
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Nf κb signaling ,Cytokine ,Chemistry ,medicine.medical_treatment ,medicine ,Research article ,Cell Biology ,Receptor ,Molecular Biology ,Biochemistry ,ESCRT ,Cell biology - Abstract
Fig. 4 and the legend for Fig. 5 have been updated.
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- 2019
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