Dissertations / Theses on the topic 'Leukemia cell'
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Cornforth, Terri Victoria. "Characterising the cell biology of leukemic stem cells in acute myeloid leukemia." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:654b2176-fd50-427e-86f2-74e928054bef.
Full textOsuji, Nnenna. "Leukemias of Mature T-Cell Phenotype with Gene Expression Profiling in T-Cell prolymphocytic Leukemia." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498887.
Full textMorisot, Sebastien. "Détermination of the frequency of leukemia stem cells in childhood precursor B cell acute lymphoblastic leukemias." Paris 11, 2009. http://www.theses.fr/2009PA11T022.
Full textCOLOMAR, CARANDO NATALIA. "Novel insights into NK cell/leukemia molecular interactions and possible tools to potentiate the anti-leukemia NK cell activity." Doctoral thesis, Università degli studi di Genova, 2022. http://hdl.handle.net/11567/1079072.
Full textPapayannidis, Cristina <1980>. "Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5596/1/TesiPapayannidisDottorato2013_Copy.pdf.
Full textPapayannidis, Cristina <1980>. "Pre-clinical and clinical development of leukemia stem cell inhibitors in acute leukemias." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2013. http://amsdottorato.unibo.it/5596/.
Full textMatsubara, Yasushi. "Delineation of immunoregulatory properties of adult T cell leukemia cells." Kyoto University, 2007. http://hdl.handle.net/2433/135653.
Full textO'Neill, Kieran. "Automated analysis of single cell leukemia data." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50867.
Full textScience, Faculty of
Graduate
Machado, Parrula Maria Cecilia. "Measles Virotherapy in Adult T cell Leukemia." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1261413581.
Full textLam, Wilbur Aaron. "Cell mechanics of leukostasis in acute leukemia." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3311343.
Full textSource: Dissertation Abstracts International, Volume: 69-06, Section: B, page: 3693. Adviser: Daniel Fletcher.
Runarsson, Gudmundur. "Biosynthesis of leukotriene B₄ in hematological malignancies /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-386-8/.
Full textIhme, Erika Ruth Susann [Verfasser]. "Characterization of the Leukemia Initiating Cell in Human Acute Myeloid Leukemia / Erika Ruth Susann Ihme." Ulm : Universität Ulm, 2016. http://d-nb.info/1126036323/34.
Full textNagai, Yuya. "T memory stem cells are the hierarchical apex of adult T-cell leukemia." Kyoto University, 2015. http://hdl.handle.net/2433/202670.
Full textDeshpande, Aniruddha. "Characterisation of the Leukemic Stem Cell in a Murine Model of CALM/AF10 Positive Myeloid Leukemia." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-57555.
Full textKokhaei, Parviz. "Preclinical therapeutic vaccination strategies in malignancies with focus on B-cell chronic lymphocytic leukemia /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-595-X/.
Full textNiu, Suli. "Quantitative Determination of Surface Markers on B-cell Chronic Lymphocytic Leukemia (CLL) Cells." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30982.
Full textCho, Candice. "Factors affecting stem cell transplantation for leukemia and lymphoma." CONNECT TO ELECTRONIC THESIS, 2006. http://hdl.handle.net/1961/3595.
Full textLanemo, Myhrinder Anna. "Restricted antigen recognition in B cell chronic lymphocytic leukemia." Licentiate thesis, Linköping University, Linköping University, Faculty of Health Sciences, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-16355.
Full textChronic lymphocytic leukemia (CLL) cells are considered to be derived from antigen-exposed B cells. To further explore the antigen-driven selection behind the leukemogenesis of CLL, we performed immunoglobulin (Ig) specificity screening of 7 CLL cell lines and 23 primary CLL clones from patient peripheral blood. We also included a recombinant monovalent monoclonal antibody (mAb) belonging to a subset of CLL cases with identical or semiidentical heavy chain complementarity determining region 3 (HCDR3) of the IGHV3-21 gene rearrangement. We found CLL mAb specificities against vimentin, filamin B, cofilin-1, proline-rich acidic protein 1, cardiolipin, oxidized low density lipoprotein and Streptococcus pneumoniae polysaccarides. These molecules are functionally associated with microbial infection and/or apoptotic cell removal. An antigen-driven selection would therefore imply that CLL B cell precursors are involved in the elimination and scavenging of pathogens and apoptotic cells, which could trigger the development of the disease.
The limited in vitro survival of CLL cells makes Epstein-Barr virus (EBV) immortalization of CLL cells a useful experimental model for studies on antibody-specificity screening. Considering the intricate procedure of EBV transformation of CLL cells and the many false cell lines used worldwide, we also wanted to characterize and evaluate the authentic origin of several previously established CLL cell lines and their normal lymphoblastoid counterparts. Three of the CLL cell lines tested were truly authentic (I83-E95, CLL-HG3 and CII), two had features of a biclonal Ig expression (232B4 and WaC3CD5+), one was only tentatively verified (PGA-1), whereas one cell line could not be verified (EHEB) due to lack of original patient cells for comparison. Two of the presumed normal lymphoblastoid cell lines tested were shown to be a neoplastic CLL clone. This study emphasizes the importance of proper cell line authentication and we will continue to verify additional cell lines not yet proven authentic.
In conclusion, we provide evidence for natural Ab production by CLL cells and suggest that these cells might be derived from B cell precursors involved in the innate immunity and, thus, providing a first-line-defence against pathogens and in elimination of apoptotic cells.
Bartlebaugh, Jordan Michael Elizabeth. "PHF6 modulates the chromatin landscape in B-cell leukemia." Thesis, Massachusetts Institute of Technology, 2018. http://hdl.handle.net/1721.1/115690.
Full textCataloged from PDF version of thesis.
Includes bibliographical references.
Developmental and lineage plasticity have been observed in numerous malignancies, and have been correlated with tumor progression and drug resistance. However, little is known about the molecular mechanisms that enable such plasticity to occur. Here, we describe the function of the Plant Homeodomain Finger Protein 6 (PHF6) in leukemia and define its role in regulating chromatin accessibility to lineage-specific transcription factors. We show that loss of Phf6 in B-cell leukemia results in systematic changes in gene expression via alteration of the chromatin landscape at the transcriptional start sites of B- and T-cell specific factors. Additionally, Phf6KO cells show significant down-regulation of genes involved in the development and function of normal B-cells, up-regulation of genes involved in T-cell signaling, and give rise to mixed-lineage lymphoma in vivo. Engagement of divergent transcriptional programs results in phenotypic plasticity that leads to altered disease presentation in vivo, tolerance of aberrant oncogenic signaling, and differential sensitivity to frontline and targeted therapies. These findings suggest that active maintenance of a precise chromatin landscape is essential for sustaining proper leukemia cell identity, and that loss of a single factor (PHF6) can cause focal changes in chromatin accessibility and nucleosome positioning that render cells susceptible to lineage transition.
by Jordan Michael Elizabeth Bartlebaugh.
Ph. D.
Valia, Dhvani. "EMERGING NATURAL KILLER CELL IMMUNOTHERAPY FOR ACUTE MYELOID LEUKEMIA." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1561938259242716.
Full textSasada, Amane. "APOBEC3G targets human T-cell leukemia virus type 1." Kyoto University, 2006. http://hdl.handle.net/2433/143870.
Full textChang, Hsu-Hsiang. "The tumor microenvironment of B-cell chronic lymphocytic leukemia." Diss., View abstract only; access to full text of dissertation for UC campuses will be available after September 1, 2010, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p1457295.
Full textTitle from first page of PDF file (viewed November 10, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 52-56).
Birerdinc, Aybike. "Role of KCNRG in B-CELL chronic lymphocytic leukemia." Fairfax, VA : George Mason University, 2008. http://hdl.handle.net/1920/3365.
Full textVita: p. 175. Thesis director: Ancha Baranova. Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Title from PDF t.p. (viewed Jan. 8, 2009). Includes bibliographical references (p. 156-174). Also issued in print.
Takeda, Satoshi. "Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cell." Kyoto University, 2004. http://hdl.handle.net/2433/147464.
Full textGupta, Sneha Veeraraghavan. "Targeting Protein Metabolism in B-cell Malignancies." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973.
Full textThörn, Ingrid. "Minimal Residual Disease Assessment in Childhood Acute Lymphoblastic Leukemia." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101028.
Full text黃傑煇 and Kit-fai Wong. "CD56-positive: natural killer cell lymphoma/leukaemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B3198177X.
Full textWong, Kit-fai. "CD56-positive natural killer cell lymphoma/leukaemia /." Hong Kong : University of Hong Kong, 2001. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23736197.
Full textMecarozzi, Marco. "Notch3 overexpression induces an alteration in Ikaros splicing mediated by the RNA-binding protein HuD in T-ALL leukemia." Doctoral thesis, La Sapienza, 2008. http://hdl.handle.net/11573/917421.
Full textFuruta, Rie. "Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo." Kyoto University, 2018. http://hdl.handle.net/2433/232110.
Full textRezvany, Mohammad Reza. "Natural specific T cell immunity in patients with B-cell chronic lymphocytic leukaemia (B-CLL) : (a clinical and immunological study) /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4841-0/.
Full textOlsson, Anna. "Molecular characterization of apoptosis in B-cell chronic lymphocytic leukemia /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-267-5/.
Full textVan, Vlierberghe Pieter. "Moleciular-genetic insights in pediatric T-cell acute lymphoblastic leukemia." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/12225.
Full textBramson, Jonathan. "Nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28690.
Full textThus, our studies indicate that nitrogen mustard resistance in B-CLL correlates with enhanced activity of a crosslink specific repair process. The observation that nitrogen mustard resistance in B-CLL is associated with cross-resistance to mitomycin C, cisplatin and ara-C, through a mechanism other than P-glycoprotein or glutathione, suggests that this model may represent a novel multi-drug resistant phenotype.
Murrell, Adele Meinie. "Transcriptional regulation and function of the stem cell leukemia gene." Thesis, University of Cambridge, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361614.
Full textManthri, Sukesh, Haroon Rehman, Rabia Zafar, and Kanishka Chakraborty. "A Rare Case of Non-Producing Primary Plasma Cell Leukemia." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/89.
Full textVockentanz, Lena. "Leukemia stem cell fates are determined by DNA methylation levels." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16321.
Full textDNA methylation is one of the major epigenetic processes which is crucially involved in orchestrating gene regulation primarily by repression of gene expression. DNA methylation plays an important role in controlling functional programs of embryonic and tissue stem cells. As altered DNA methylation patterns are a hallmark of cancer, we hypothesized that DNA methylation might be equally important for cell fate determinations of cancer stem/initiating cells (CSC). To test this, I analyzed a genetic knockdown mouse model of the main somatic DNA methyltransferase Dnmt1 in the context of three different leukemia models. In a bilinear B-lymphoid/myeloid leukemia model hypomethylated bi-potential leukemia stem/initiating cells (LSCs) were shown to be capable of forming a myeloid leukemia, whereas the generation of B-lymphoid blasts was almost entirely abrogated. Moreover, failure of hypomethylated cells to develop T-cell lymphomas in a Notch1-based leukemia model demonstrated their profound lack of T-lineage commitment capacities. Furthermore, detailed analyses of a myeloid leukemia model revealed a severely impaired self-renewal potential in LSCs with reduced Dnmt1 expression. However, contrasting the drastic cell-intrinsic impairments of LSC function by reduced DNA methylation, leukemia development was found to be unaffected by hypomethylated bone marrow stroma. Mechanistically, treatment of cell lines with a demethylating drug led to enhanced expression of differentiation factors due to loss of methylation mediated gene silencing. This was followed by inhibition of leukemia cell growth, thus providing a potential mechanism for impaired functions of hypomethylated leukemias. Collectively, this thesis revealed a critical role for DNA methylation levels in malignant self-renewal and lineage fate choices. These new insights into epigenetic regulation of CSCs suggest that epigenetic therapy displays a potential treatment concept specifically targeting CSCs.
Passeri, Francesca. "T-CELL LARGE GRANULAR LYMPHOCYTE LEUKEMIA: PATHOGENESIS AND MOLECULAR DEVELOPMENT." Doctoral thesis, Università degli studi di Padova, 2014. http://hdl.handle.net/11577/3424598.
Full textLa malattia linfoproliferativa dei linfociti granulati (LGLL) è una malattia rara caratterizzata da una linfocitosi cronica dei grandi linfociti granulati (LGL) con attività citotossica. Da un punto di vista immunologico, si distinguono due forme di LGLL: La T-LGLL, caratterizzata dalla proliferazione di LGL di tipo T, nonché forma più frequente della patologia (~85% dei casi) e la NK-CLPD, più rara (~15% dei casi) in cui la linfocitosi viene sostenuta da cellule di tipo NK. L’eziopatogenesi della T-LGLL risulta essere ancora materia di dibattito. L’ipotesi più accreditata indica la stimolazione antigenica come evento in grado di attivare gli LGL; queste cellule intraprendono dunque un’espansione clonale, che viene mantenuta in un secondo tempo dal consistente rilascio di citochine (prevalentemente IL-6 ed IL-15) e da un equilibrio vita/morte cellulare alterato, generato quest’ultimo dalla contemporanea attivazione di numerose vie di sopravvivenza cellulare. Nel nostro laboratorio abbiamo seguito differenti linee di ricerca, con l’obiettivo di verificare tale ipotesi eziopatogenica e trovare nuovi target terapeutici. Abbiamo preso prima di tutto in considerazione la via di segnale JAK/STAT, che si riporta essere alterata nella T-LGLL. Ci siamo soffermati in particolare sulla proteina STAT3, che risulta essere costitutivamente attivata, e su SOCS3, suo specifico inibitore, emerso essere, dai nostri studi, down-espresso e non responsivo all’IL-6 nella T-LGLL. Le basi fisiologiche determinanti il mancato meccanismo a feed-back negativo di SOCS3 non risultano ancora definite, dal momento che il promotore di SOCS3 non è risultato essere regolato tramite metilazione; è possibile tuttavia che un meccanismo epigenetico sia comunque responsabile dell’alterata regolazione della via di segnale JAK/STAT, in quanto abbiamo osservato che l’uso di un agente demetilante è in grado di ripristinare l’attività inibitoria di SOCS3. Abbiamo quindi analizzato il principale attivatore dell’asse STAT3/SOCS3, ovvero l’interleuchina 6 (IL-6), evidenziando come tramite l’attivazione di STAT3 essa sia in grado di promuovere la sopravvivenza degli LGL. Abbiamo inoltre rilevato che tale citochina è espressa in particolar modo dai PBMC non LGL di pazienti caratterizzati da bassi livelli di LGL circolanti (<55%). Il coinvolgimento di IL-6 nella sopravvivenza degli LGL è stato confermato da un’induzione dell’apoptosi in seguito a coltura con anticorpi bloccanti anti-IL-6 ed anti-IL-6Rα (recettore α dell’IL-6), dovuta ad una riduzione dei livelli di STAT3 attivata. Passaggio successivo è stato analizzare il sistema recettoriale di IL-6, composto da due differenti catene: IL-6Rα e gpl30. I dati ottenuti suggeriscono un meccanismo di trans-signaling, particolarmente coinvolto nei processi di tipo infiammatorio, alla base dell’azione di IL-6 nella T-LGLL; IL-6Rα è presente infatti ad alti livelli nel plasma dei pazienti, pur venendo scarsamente espresso dagli LGL. Tra i geni target di STAT3 vi è CLL5, un potente agente chemotattico che si riporta essere over-espresso nella T-LGLL; nel nostro laboratorio abbiamo osservato inoltre che la sua espressione è responsiva allo stimolo con IL-6. Dal momento che il midollo osseo dei pazienti risulta essere frequentemente infiltrato dagli LGL e che le cellule mesenchimali stromali (BM-MSCs) risultano essere una presunta fonte di IL-6, abbiamo analizzato il ruolo di queste cellule nella T-LGLL e dimostrato che esse sono in grado di promuovere la sopravvivenza degli LGL e probabilmente stimolare l’espressione di CCL5 da parte degli LGL, tramite il rilascio di IL-6. Abbiamo studiato l’interleuchina 15 (IL-15), una citochina chiave della T-LGLL espressa in particolar modo dalle cellule dendritiche (DC) dei pazienti, considerate responsabili dell’attivazione degli LGL tramite presentazione dell’antigene. Abbiamo analizzato gli effetti di IL-15 sul signaling di IL-6 ed abbiamo evidenziato come tale citochina sia in grado di promuovere il meccanismo di trans-signaling attraverso l’induzione d’espressione di IL-6 nei PBMC dei pazienti e l’inibizione dell’espressione di IL-6Rα negli LGL. Dati recenti di letteratura riportano, infine, hot spot mutazionali nel dominio SH2 di STAT3; è stato ipotizzato che la costitutiva attivazione di STAT3 sia dovuta a tali mutazioni, per tale motivo abbiamo indagato, nella nostra coorte di pazienti, la presenza delle mutazioni descritte finora riportate in letteratura. Abbiamo riscontrato le due mutazioni, D661Y e Y640F, sono presenti in circa 20% dei casi e specificamente in pazienti caratterizzati da un’alta percentuale di LGL circolanti (>55%), che costituiscono il 40% dei casi con LGLL.
Flores, Violante Mario. "Role of the Bone Morphogenetic Proteins pathway in leukemic stem cell regulation and resistance in acute myeloid leukemia." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1118/document.
Full textAcute myeloid leukemias (AML) are heterogeneous hematological malignancies characterized by a clonal proliferation of myeloid blasts which infiltrate the bone marrow, blood and other organs. Identified as the most common type of acute leukemia in adults with 80% of cases, AML is associated with high relapse and poor prognosis where 70% of patients face mortality within one year after diagnosis. Leukemic stem cell (LSCs) presence has been related to resistance to chemotherapeutic agents and relapse in AML. The tumor microenvironment has been described for its key role regulating LSCs through the crosstalk of signaling pathways. Bone Morphogenetic Proteins (BMP) pathway is highly involved in hematopoietic stem cell (HSC) regulation, but has also been recognized to regulate LSCs. Here, we have identified high concentrations of BMP2 and BMP4 in bone marrow (BM) AML samples at diagnosis. Furthermore, we have identified for the first time a new signaling cascade, involving the binding of BMP4 to BMPR1A receptor, which induces the expression of ΔNp73 and NANOG. Activation of this signaling promotes a stem-like phenotype in leukemic cells. Therefore, we hypothesized that this signaling is responsible for the resistant capacity of leukemic cells to chemotherapy. In addition, we have reported BMPR1A/ΔNp73/NANOG as potential AML prognosis markers, due to their overexpression at diagnosis associated to an increased rate of relapse of AML patients within three years. When we analyzed AML samples at relapse, higher levels of ΔNp73 isoform were found compared to patients at diagnosis. Moreover, we have identified high expression of the BMPR1A receptor, ΔNp73, NANOG, SOX2 and ID1 in short-term resistant primary leukemic cells. These results correlate with what we observed in AML resistant cells, where BMPR1A, ΔNp73, NANOG and ID1 seem to be implicated in driving the resistant capacity of AML cells to drug therapy. Therefore, modulation and targeting of the BMP pathway elements and related genes identified with our study, represent a promising approach towards the development of new and more effective therapeutic strategies against AML
Ehinger, Mats. "On the role of the tumor suppressor gene p53 in leukemic cell differentiation." Lund : Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945098.html.
Full textSun, Qian. "Cellular and molecular mechanisms of dendritic cell differentiation from cells of leukaemic origin." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38885335.
Full textHing, Zachary Andrew. "Targeting Nuclear Export in Chronic Lymphocytic Leukemia." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313.
Full textWatson, Alexander Scarth. "Autophagy in hematopoiesis and acute myeloid leukemia." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2e66c5c3-4774-44d1-8345-d0dc827da16d.
Full textHammarsund, Marianne. "Genetic changes in lymphoid leukemia /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-628-5841-6/.
Full textGottardo, Nicholas G. "Oncogenes and prognosis in childhood T-cell acute lymphoblastic leukaemia." University of Western Australia. School of Paediatrics and Child Health, 2008. http://theses.library.uwa.edu.au/adt-WU2009.0039.
Full textNordström, Marie. "Epidemiological aspects on hairy cell leukaemia /." Linköping : Univ, 1999. http://www.bibl.liu.se/liupubl/disp/disp99/Med592s.htm.
Full textHiraragi, Hajime. "Study of lentiviral vector for in utero gene transfer and functional analysis of human T-lymphotropic virus type p13(II)." Connect to resource, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1116532636.
Full textTitle from first page of PDF file. Document formatted into pages; contains xvii, 230 p.; also includes graphics. Includes bibliographical references (p. 200-230). Available online via OhioLINK's ETD Center
Orlandi, Veronica. "Effects of p66shc expression on bioenergetics and cell viability of b-cell chronic lymphocytic leukemia." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3423953.
Full textDurante lo sviluppo tumorale, molte vie di segnale delle cellule vengono riprogrammate cambiando il metabolismo mitocondriale e diminuendo l’attività della fosforilazione ossidativa. In questa maniera viene diminuita la produzione di ATP e di ROS da parte della fosforilazione ossidativa favorendo un metabolismo glicolitico e la crescita tumorale. I meccanismi alla base dello sviluppo di questo fenotipo sono ben caratterizzati nelle cellule di tumori solidi, ma poco si sa a riguardo delle leucemie. Nella leucemia linfocitica cronica, le cellule presentano elevata attività OXPHOS e alti livelli di ROS. È noto che la proteina p66Shc, di cui una frazione si trova nello spazio intermembrana del mitocondrio, modula la bioenergetica cellulare e induce la produzione di ROS. Durante il processo di tumorigenesi della B-CLL l’espressione di p66Shc viene persa. Quindi, sono andata ad analizzare l’effetto della espressione di p66Shc sulla bioenergetica e la vitalità cellulare della leucemia linfocitica cronica. Dopo l’espressione di p66Shc nel modello cellulare di leucemia linfocitica cronica di tipo B, MEC-1, una frazione della proteina è stata trovata nello spazio intermembrana dei mitocondri. L’espressione di p66Shc nelle cellule diminuisce la respirazione mitocondriale, massima e basale, ma anche il potenziale di membrana e i livelli totali di ATP. Ho proposto che queste differenze sono dovute alla diminuzione dell’attività dei complessi respiratori: complesso I e complesso II indotta dalla espressione di p66Shc nelle cellule MEC-1. In particolare, il complesso I è meno assemblato con la conseguente diminuzione della sua attività mentre il complesso II diminuisce la sua attività a causa di un complesso multi proteico in cui sono coinvolti la proteina chinasi ERK e lo sciaperone mitocondriale TRAP1. L’espressione di p66Shc nelle MEC-1 aumenta l’attivazione della frazione mitocondriale di ERK. Questa frazione, contribuisce alla sopravvivenza delle cellule tumorali inibendo l’apertura del poro di transizione di permeabilità (mPTP), un canale mitocondriale la cui apertura porta alla morte cellulare. Ho quindi analizzato l’effetto dell’espressione di p66Shc sulla vitalità cellulare delle MEC-1. Sebbene, p66Shc ha una attività pro-apoptotica, ho osservato che la sua espressione nelle MEC-1 protegge le cellule dalla morte cellulare indotta dallo stress ossidativo prodotto dal mitocondrio da trattamenti come EM20-25, CisPlatino e assenza di glucosio. In assenza di glucosio, l’espressione di p66Shc correla con una maggiore attivazione di ERK nel mitocondrio. L’inibizione di ERK diminuisce la vitalità cellulare. In assenza di glucosio, anche l’inibizione degli sciaperoni mitocondriali CyP-D e TRAP1 influenzano la vitalità cellulare. Quindi, la frazione mitocondriale di ERK è coinvolta nella regolazione delle vie di segnale che proteggono le cellule dalla morte cellulare dopo l’espressione di p66SHhc. Questi dati, indicano che la regolazione dell’attività dei complessi respiratori è legata alla regolazione della sopravvivenza cellulare. Abbiamo ipotizzato che nella leucemia linfocitica cronica la parte mitocondriale della via di segnale RAS-ERK può regolare la bioenergetica influenzando l’attività enzimatica del complesso II e la resistenza alla morte cellulare. Inoltre, abbiamo ipotizzato anche una nuova funzione per p66Shc in cui, attraverso l’attivazione di ERK e l’inibizione dell’attività del complesso II può diminuire l’attività della fosforilazione ossidativa e i livelli di ROS, una condizione necessaria nelle prime fasi della tumori genesi. p66Shc può anche sostenere la crescita tumorale rendendo mPTP meno sensibile all’apertura attraverso l’attivazione della frazione mitochondrial di ERK.
Weyden, Louise van der. "ATP-stimulated white cell maturation via the P2Y₁₁ receptors and cAMP signaling pathway." Thesis, The University of Sydney, 2001. https://hdl.handle.net/2123/28067.
Full textDielschneider, Rebecca. "Targeting Susceptible Signaling Pathways in Chronic Lymphocytic Leukemia." Cell Death and Disease, 2014. http://hdl.handle.net/1993/31681.
Full textOctober 2016