Thèses : « Leukemia cell »

1

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.

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Acute Myeloid leukemia (AML) is an aggressive haematological malignancy that mainly affects the elderly. Relapse is common and is thought to be due to the presence of chemotherapy resistant leukemic stem cells (LSC). Within the CD34+ disease (>5% of the blast cells expressing CD34) , two subtypes have been identified; an LMPP/GMPlike expanded type and a MPP/CMP-like expanded type, the former is the most common, accounting for around 80% of CD34+ AML. Both the GMP-like and LMPPlike expanded populations show LSC activity. To improve our understanding of the disease and gain better insight in to how to develop treatments, the molecular basis of the disease needs to be investigated. I investigated miRNAs in the GMP/LMPP-like expanded AML. miRNAs are small non-coding RNAs involved in the regulation of mRNA. In recent years miRNAs have been shown to be implicated in many different diseases. To investigate the role miRNAs play in AML, miRNA expression was profiled in leukemic and normal bone marrow. Bioinformatic analysis was then used to examine the different miRNA expression profiles between normal and leukemic marrow. Our study showed that miRNAs are dysregulated in AML. miRNAs from the miR-17-92 and its paralogous cluster miR-106b-92 were amongst the miRNAs to be found down regulated in AML As had been seen previously at an mRNA level, on an miRNA level the LSC populations more closely resembled more mature progenitor populations than HSC and MPP populations, however the LSC populations did display an aberrant stem cell-like miRNA signature.

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2

Osuji, 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.

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3

Morisot, 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.

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4

COLOMAR, 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.

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Natural killer (NK) cells are extremely promising for cellular antitumor therapy in terms of efficacy and safety, particularly in the control of hematological malignancies. The aim of this thesis was to provide deeper insights on receptor/ligand leukemia interactions and investigate possible tools to enhance the NK cell anti-leukemia activity. Two clinical contexts of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) were under evaluation 1) αβT-cell and B-cell depleted haplo-HSCT in pediatric leukemia patients, and 2) haplo-HSCT with post-transplant cyclophosphamide (PT-Cy) in adult AML patients. Regarding the first platform, we tested the in vitro effect of different NK cell engagers (NKCEs), which can trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). We used as target cells different BCP-ALL cell lines and primary leukemias, and as effector cells resting NK cells derived from healthy donors and pediatric leukemia patients after αβT/B-depleted haplo-HSCT. The NKCEs potentiated the killing of NK-cell resistant BCP-ALL cells and enhanced the degranulation and cytokine production of NK cells. These data strongly support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight relapsed/refractory leukemia in pre- or post-transplantation setting. Regarding the other platform, we investigated the phenotype of NK cells after transplantation, and we evaluated the effect of immune checkpoint inhibitor (ICI), targeting NKG2A, to unleash NK-cell activity against leukemia. The data pave the way for the use of an anti-NKG2A antibody (as Monalizumab) at early-time points after transplantation to enhance the anti-leukemia activity of NK cells.

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5

Papayannidis, Cristina <1980&gt. « 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.

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In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.

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6

Papayannidis, Cristina <1980&gt. « 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/.

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In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy.

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7

Matsubara, Yasushi. « Delineation of immunoregulatory properties of adult T cell leukemia cells ». Kyoto University, 2007. http://hdl.handle.net/2433/135653.

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8

O'Neill, Kieran. « Automated analysis of single cell leukemia data ». Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50867.

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Acute myeloid leukemia (AML) is a high grade malignancy of non-lymphoid cells of the hematopoietic system. AML is a heterogeneous disease, and numerous attempts have been made to risk-stratify AML so that appropriate treatment can be offered. Single cell analysis methods could provide insights into the biology of AML leading to risk-stratified and functionally tailored treatments and hence improved outcomes. Recent advances in flow cytometry allow the simultaneous measurement of up to 17 antibody markers per cell for up to millions of cells, and it is performed routinely during AML clinical workup. However, despite vast amounts of flow cytometry data being gathered, comprehensive, objective and automated studies of this data have not been undertaken. Another method, strand-seq, elucidates template strand inheritance in single cells, with a range of potential applications, none of which had been automated when this thesis work commenced. I have developed bioinformatic methods enabling research into AML using both these types of data. I present flowBin, a method for faithfully recombining multitube flow cytometry data. I present flowType-DP, a new version of flowType, able to process flow cytometry and other single cell data having more than 12 markers (including flowBin output). I demonstrate the application of flowBin to AML data, for digitally isolating abnormal cells, and classifying AML patients. I also use flowBin in conjunction with flowType to find cell types associated with clinically relevant gene mutations in AML. I present BAIT, a software package for accurately detecting sister chromatid exchanges in strand-seq data. I present functionality to place unbridged contigs in late-build genomes into their correct location, and have, with collaborators, published the corrected locations of more than half the unplaced contigs in the current build of the mouse genome. I present contiBAIT, a software package for assembling early-build genomes which consist entirely of unanchored, unbridged contigs. ContiBAIT has the potential to dramatically improve the quality of many model organism genomes at low cost. These developments enable rapid, automated, objective and reproducible deep profiling of AML flow cytometry data, subclonal cell analysis of AML cytogenetics, and improvements to model organisms used in AML research.
Science, Faculty of
Graduate

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9

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.

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10

Lam, 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.

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Thesis (Ph.D.)--University of California, San Francisco with the University of California, Berkeley, 2008.
Source: Dissertation Abstracts International, Volume: 69-06, Section: B, page: 3693. Adviser: Daniel Fletcher.

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11

Runarsson, Gudmundur. « Biosynthesis of leukotriene B₄ in hematological malignancies / ». Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-386-8/.

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12

Ihme, 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.

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13

Nagai, Yuya. « T memory stem cells are the hierarchical apex of adult T-cell leukemia ». Kyoto University, 2015. http://hdl.handle.net/2433/202670.

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14

Deshpande, 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.

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15

Kokhaei, 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/.

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16

Niu, 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.

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To supplement and modify the diagnosis and clinical research of B-cell Chronic Lymphocytic Leukemia (B-CLL), a new method based on cell imaging and image processing was developed and applied to the B-CLL patient samples. The fluorophore-labelled leukemia cells were clearly visualized, reflecting the positive/negative expression of the corresponding surface markers and their distribution. Computer algorithms were devised and used to analyze a large number of images. The fluorescence intensity of the labelled antibodies on a given cell directly reflects the expression of the corresponding surface markers. The morphology and size of leukemia cells were not identical even in the same patient’s sample and the size variation does not correlate with the number of surface markers. The amount of each surface marker was approximately fixed for each patient, but there were some relationships, for instance, the number of CD19 and CD38 markers were correlated to each other. The heterogeneous expression of surface markers confirmed an assumption that surface markers have their preferred membrane positions. One of the most important results is that the cell imaging and our image processing method has provided an alternative and reliable way to diagnose B-CLL and new insights in the prognosis of subtype of B-CLL.

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17

Cho, Candice. « Factors affecting stem cell transplantation for leukemia and lymphoma ». CONNECT TO ELECTRONIC THESIS, 2006. http://hdl.handle.net/1961/3595.

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18

Lanemo, 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.

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Chronic 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.

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19

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.

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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2018.
Cataloged 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.

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20

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.

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21

Sasada, Amane. « APOBEC3G targets human T-cell leukemia virus type 1 ». Kyoto University, 2006. http://hdl.handle.net/2433/143870.

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22

Chang, 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.

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Thesis (M.S.)--University of California, San Diego, 2008.
Title from first page of PDF file (viewed November 10, 2008). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 52-56).

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23

Birerdinc, Aybike. « Role of KCNRG in B-CELL chronic lymphocytic leukemia ». Fairfax, VA : George Mason University, 2008. http://hdl.handle.net/1920/3365.

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Thesis (Ph.D.)--George Mason University, 2008.
Vita: 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.

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24

Takeda, Satoshi. « Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cell ». Kyoto University, 2004. http://hdl.handle.net/2433/147464.

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25

Gupta, Sneha Veeraraghavan. « Targeting Protein Metabolism in B-cell Malignancies ». The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343169973.

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26

Thörn, 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.

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27

黃傑煇 et 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.

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Wong, 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.

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29

Mecarozzi, 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.

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30

Furuta, Rie. « Human T-cell leukemia virus type 1 infects multiple lineage hematopoietic cells in vivo ». Kyoto University, 2018. http://hdl.handle.net/2433/232110.

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31

Rezvany, 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/.

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32

Olsson, Anna. « Molecular characterization of apoptosis in B-cell chronic lymphocytic leukemia / ». Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-267-5/.

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33

Van, 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.

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34

Bramson, 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.

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Previous studies of nitrogen mustard drug resistance in B-cell chronic lymphocytic leukemia (B-CLL) indicated that resistance was a result of enhanced DNA repair associated with increased expression of two DNA repair genes, ERCC-1 and alkyl-N-purine DNA glycosylase. The aim of this thesis was to expand upon these observations and solidify the link between DNA repair and nitrogen mustard drug resistance. Contrary to our expectations, overexpression of ERCC-1 in CHO cells produced increased sensitivity to melphalan and cisplatin. No correlation was found between ERCC-1 expression and nitrogen mustard resistance in B-CLL, when analyzed in a larger cohort by both Northern and western blots, nor was there evidence of altered expression of a second nucleotide excision repair gene (NER), ERCC-2. Overexpression of alkyl-N-purine DNA glycosylase in CHO cells failed to produce melphalan resistance. Nitrogen mustard resistant B-CLL lymphocytes displayed cross-resistance to the bifunctional agents, mitomycin C and cisplatin, but not to UV or methyl methanesulfonate, supporting a role for enhanced crosslink repair in the resistant phenotype. Poly(ADP-ribose) polymerase (PARP) has been identified as a binding protein which can recognize melphalan damaged DNA. This binding appears to result from nicks induced by the melphalan treatment and can be inhibited if the DNA is alkylated with melphalan in the presence of methoxyamine. PARP expression was the same in both sensitive and resistant lymphocytes. When 3-aminobenzamide was used to inhibit PARP, synergy with melphalan was found in 4 of 7 samples we studied. When the DNA synthesis inhibitors, aphidicolin and ara-C, were used to modulate chlorambucil toxicity, synergy was found in both sensitive and resistant populations. There was also evidence for cross-resistance between chlorambucil and ara-C.
Thus, 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.

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35

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.

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Manthri, Sukesh, Haroon Rehman, Rabia Zafar et 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.

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Non-Secretory Multiple Myeloma (NSMM) is characterized by typical morphological and pathological multiple myeloma (MM) characteristics and the absence of an M-protein on immunofixation electrophoresis with estimated prevalence of 3%. Among the NSMM cases there is a subset in which no cytoplasmic Immunoglobulin synthesis is detected, and this entity is called ‘’Non-Producing’’ Multiple Myeloma (NPMM). Plasma cell leukemia (PCL) is an aggressive form of MM characterized by high levels of abnormal plasma cells circulating in the peripheral blood. We present a rare case of non-producing variant of PCL. 75-year-old male was admitted due to anemia and thrombocytopenia. His CBC revealed hemoglobin of 9.0 g/dl and platelets were 9 k/ul. CMP showed creatinine of 1.34 mg/dl, total protein of 6 g/dl, albumin 3.6 g/dl and corrected calcium was normal. LDH was 204 IU/L. Peripheral smear review showed 8% circulating atypical plasmacytoid cells, normochromic normocytic anemia and thrombocytopenia. SPEP showed no monoclonal protein. IgA was normal. IgG, IgM were low 315 mg/dl and 20 mg/dl respectively. Serum beta-2 microglobulin was high (5.5, 1.1 – 2.4 mg/dl). Serum free kappa light chain was low (0.15, 0.33-1.94 mg/dl), lambda light chain and ratio was normal. Skeletal survey showed possible lytic lesions in right femur neck and subtrochanteric left femur. Bone marrow biopsy showed plasma cell myeloma involving 90-95% of bone marrow cellularity. The plasma cells show morphologic heterogeneity with prominent immature, plasmablastic and pleomorphic morphology. Flow cytometry shows a dominant abnormal CD45-dim population with expression of CD38, CD138, CD56 and CD117 (partial). The abnormal cells are negative for cytoplasmic kappa and lambda immunoglobulin light chains and negative for myeloid and lymphoid markers (by flow cytometry and immunohistochemical stains). Complex chromosomal analysis. Plasma cell FISH studies was positive for t(11;14). Based on suggested revised diagnostic criteria for PCL from outcomes of patients at mayo clinic, our patient was diagnosed with plasma cell leukemia. Given aggressive biology of this disease, he was started on VD-PACE chemotherapy. Bone marrow biopsy after cycle 1 chemotherapy showed no morphologic, immunophenotypic or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response and discussion with transplant center subsequent cycle 2 was changed to Velcade, Revlimid and low-dose dexamethasone. He is scheduled for stem cell transplant later this month. Primary plasma cell leukemia (pPCL) is the most aggressive form of the plasma cell dyscrasias. The outcome of pPCL has improved with the introduction of autologous stem cell transplantation and combination approaches with novel agents, including bortezomib and immunomodulatory drugs, such as lenalidomide. This case highlights the challenges in diagnosis of non-producer primary plasma cell leukemia.

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Vockentanz, 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.

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DNA Methylierung ist ein zentraler epigenetischer Prozess, welcher entscheidend an der Organisation von Genregulation beteiligt ist. Dieser Vorgang ist wichtig für die Funktion sowohl von embryonalen als auch von Gewebs-Stammzellen. Krebszellen weisen häufig veränderte DNA Methylierungsmuster auf, was auf eine ähnlich wesentliche Rolle der DNA Methylierung in Krebsstammzellen (KSZ) hindeutet. Diese These wurde hier mit Hilfe eines Mausmodells mit verringerter Expression der DNA Methyltransferase Dnmt1 anhand verschiedener Leukämiemodelle untersucht. In einem bi-linearen B-lymphatischen/myeloischen Leukämiemodell konnte gezeigt werden, dass hypomethylierte leukämieinitiierende (Stamm-)zellen (LSZ) myeloische Krebszellen hervorbringen, allerdings nicht zur Bildung von B-lymphatischen Leukämiezellen befähigt sind. Darüber hinaus konnte in einem T-Zell-spezifischen Leukämiemodell gezeigt werden, dass reduzierte Dnmt1 Expression nicht mit der Bildung von T-Zelllymphomen vereinbar ist. Detaillierte Analysen eines myeloischen Leukämiemodells ergaben, dass hypomethylierte LSZs ein vermindertes Selbsterneuerungspotenzial aufweisen. Im Gegensatz zu den starken Funktionseinschränkungen hypomethylierter LSZs, hatten hypomethylierte Knochenmarks-Stromazellen keinen Effekt auf die Entwicklung von Leukämien. Außerdem führte die Behandlung leukämischer Zellen mit demethylierenden Agenzien zu einer teilweisen Aufhebung methylierungsvermittelter Genrepression. Die dadurch verstärkte Expression von Differenzierungsfaktoren verminderte das Leukämiewachstum, was einen möglichen Erklärungsansatz für das eingeschränkte Potenzial hypomethylierter Leukämien darstellt. Diese Ergebnisse demonstrieren eine zentrale Rolle der DNA Methylierung für die Selbsterneuerung und Linienwahl von LSZs, und erlauben somit neue Einblicke in die epigenetische Regulation von KSZs. Diese Erkenntnisse implizieren, dass KSZs möglicherweise ein geeignetes Ziel für epigenetische Therapieansätze darstellen.
DNA 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.

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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.

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Large granular lymphocyte leukemia (LGLL) is a rare and heterogeneous lymphoproliferative disorder characterized by the chronic proliferation of clonal large granular lymphocytes (LGLs) with cytotoxic activity. Two subtypes of LGL proliferations are distinguished: the most common type (~85% of cases), T-LGL Leukemia (T-LGLL), is sustained by T-cells and the rarer type (~15% of cases), Chronic Lymphoproliferative Disorder of Natural Killer cells (CLPD-NK), sustained by NK-cells. This PhD will focus on the T-LGL Leukemia. The etiology of T-LGLL still remains matter of debate. The main hypothesis suggests an antigenic stimulation as initial step activating LGLs, which undergo a clonal expansion then maintained by the abnormal release of cytokines (mainly IL-6 and IL-15) and by an impairment of the apoptotic machinery due to the activation of several survival pathways. The project developed in this PhD was aimed to better define this etiopathogenetic hypothesis and to find new therapeutic targets. First of all, we have taken into account the JAK/STAT pathway, reported to be deregulated in T-LGLL. We focused on STAT3, constitutively activated in LGLs, and its specific inhibitor SOCS3, that we found to be down-expressed and unresponsive to IL-6 triggering. The pathophysiology of this mechanism is unclear, since we found no methylation in SOCS3 promoter region; anyway we still hypothesize an epigenetic mechanism, since the use of a demethylating agent restored SOCS3 responsiveness. We then focused our attention on the main activator of STAT3/SOCS3 axis, IL-6, and we observed that it enhances LGL survival through STAT3 phosphorylation. We also provided evidence that IL-6 is mainly expressed by LGLs-depleted PBMC population of T-LGLL patients characterized by low levels of circulating LGLs (<55%). The involvement of IL-6 in leukemic LGL survival was confirmed by the observation that incubation with anti-IL-6 and anti-IL-6Rα (IL-6 receptor) induced apoptosis in LGLs, likely related to a reduction of STAT3 phosphorylation. The next step was the analysis of IL-6 receptor system that is composed of two functionally different chains: IL-6Rα and gpl30. Our data suggested that IL-6 acts through a trans-signaling mechanism in T-LGLL, being IL-6Rα highly detected in patients’ plasma and poorly expressed by LGLs. Interestingly, trans-signaling is peculiarly implicated in inflammatory disease. Among STAT3 target genes, CCL5 is a chemotactic agent reported to be over-expressed in LGL leukemia. In our lab we found that its expression is responsive to IL-6 stimulus. Since the BM of patients is frequently infiltrated by LGLs and mesenchymal stromal cells (BM-MSCs) are reported to be a putative source of IL-6, we studied their role in T-LGLL and demonstrated that they promote LGL survival and may trigger CCL5 expression in LGLs, through IL-6 release. We then focused on IL-15, a T-LGLL key cytokine mainly expressed by T-LGLL patients’ dendritic cells (DC), these latter being considered the responsible for LGL activation through antigen presentation. We studied IL-15 effects on IL-6 signaling and we found that this cytokine promotes the trans-signaling mechanism through an enhanced IL-6 expression by patients’ PBMCs and the inhibition of IL-6Rα expression by LGLs. Finally, recent data in the literature reported mutational hot spots in SH2 domain of STAT3, suggesting that STAT3 constitutive activation may result from these acquired genetic mutations. Accordingly, we analyzed whether patients’ LGLs showed any of STAT3 hot spot mutations up to now quoted. We observed that two mutations, D661Y and Y640F, were detected in nearly 20% of cases and more specifically in patients characterized by a high percentage of circulating LGLs (>55% ), accounting for 40% of all LGL cohort.
La 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.

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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.

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Les leucémies aiguës myéloïdes (LAM) sont des maladies hématologiques hétérogènes caractérisées par une prolifération clonale des blastes myéloïdes qui s’infiltrent dans la moelle osseuse (MO), le sang et d’autres organes. Identifiée comme le type le plus courant de leucémie aiguë chez l’adulte avec 80% des cas, la LAM est synonyme de rechute et de mauvais pronostic, avec 70% des patients étant confrontés à une mortalité dans l’année suivant le diagnostic. La présence des cellules souches leucémiques (CSL) a été associée à une résistance à la chimiothérapie et à une rechute dans la LAM. Le microenvironnement tumoral a été décrit pour son rôle clé dans la régulation des CSL par l’interaction des voies de signalisation. La voie des Bone Morphogenetic Proteins (BMP) est fortement impliquée dans la régulation des cellules souches hématopoïétiques (CSH), mais elle a également été reconnue pour réguler les CSL. Ici, nous avons identifié des concentrations élevées de BMP2 et BMP4 dans la MO des patients atteints de LAM au moment du diagnostic. De plus, nous avons identifié pour la première fois une nouvelle cascade de signalisation impliquant la liaison de BMP4 au récepteur BMPR1A, qui induit l’expression de ΔNp73 et NANOG. L’activation de cette signalisation favorise un phénotype proche des cellules souches dans les cellules leucémiques. Par conséquent, nous avons émis l’hypothèse que cette voie est responsable de la capacité de résistance des cellules leucémiques à la chimiothérapie. En outre, nous avons identifié BMPR1A/ΔNp73/NANOG comme marqueurs potentiels du pronostic dans la LAM, en raison de leurs surexpressions au moment du diagnostic associé à une rechute dans les trois ans. Lorsque nous avons analysé des échantillons de LAM lors d’une rechute, nous avons constaté des taux plus élevés de l’isoforme ΔNp73 par rapport à ceux de patients au moment du diagnostic. D’autre part, nous avons identifié une forte expression du récepteur BMPR1A, ΔNp73, NANOG, SOX2 et ID1 dans les cellules leucémiques primaires résistantes à court terme. Ces résultats sont en corrélation avec ce que nous avons observé dans les cellules résistantes de LAM, où BMPR1A, ΔNp73, NANOG et ID1 semblent être impliqués dans la capacité de résistance des cellules de LAM face à la chimiothérapie. La modulation et le ciblage des éléments de la voie BMP et des gènes associés identifiés au travers de notre étude représentent donc une approche prometteuse pour le développement de stratégies thérapeutiques innovantes et plus efficaces contre les LAM
Acute 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

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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.

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Sun, 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.

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Hing, Zachary Andrew. « Targeting Nuclear Export in Chronic Lymphocytic Leukemia ». The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523543484958313.

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Watson, 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.

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Acute myeloid leukemia (AML) develops following oncogenic alterations to hematopoietic stem (HSC) and progenitor cells (HSPCs) in the bone marrow, resulting in dysregulated proliferation of immature myeloid progenitors that interferes with normal hematopoiesis. Understanding the mechanisms of HSPC protection against damage and excessive division, and how these pathways are altered during leukemic progression, is vital for establishing effective therapies. Here, we show that autophagy, a lysosomal degradation pathway, is increased in HSPCs using a novel imaging flow cytometry autophagy assay. Loss of hematopoietic autophagy following deletion of key gene Atg5 resulted in increased HSC proliferation, leading to HSC exhaustion and bone marrow failure. Although erythrocyte and lymphocyte populations were negatively impacted by autophagy loss, myeloid cells showing immature characteristics were expanded. Deletion of Atg5 in an AML model resulted in increased proliferation under metabolic stress, dependent on the glycolytic pathway, and aberrant upstream mTOR signaling. Moreover, modulation of Atg5 altered leukemic response to culture with stromal cells. Finally, primary AML cells displayed multiple markers of decreased autophagy. These data suggest a role for autophagy in preserving HSC function, partially through suppression of HSPC proliferation, and indicate that decreased autophagy may benefit AML cells. We postulate that modulation of autophagy could help maintain stem cell function, for example during transplantation, and aid AML therapy in a setting-specific manner.

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Hammarsund, Marianne. « Genetic changes in lymphoid leukemia / ». Stockholm, 2003. http://diss.kib.ki.se/2003/91-628-5841-6/.

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Gottardo, 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.

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[Truncated abstract] The treatment of childhood acute lymphoblastic leukaemia (ALL) is one of the great success stories of paediatric oncology, transforming a universally fatal disease into one where 75 to 90% of children are now cured. Although in the past survival for children with T-cell ALL (T-ALL) lagged behind that of children with pre-B ALL, the use of contemporary intensified treatment strategies has significantly diminished this difference, with many investigators reporting similar cure rates for both groups of patients. Despite these marked improvements, numerous challenges still face physicians treating children with T-ALL. Firstly, there have been no additional major improvements in outcome over the last decade, despite additional treatment intensification. Secondly, effective regimens remain elusive for treating children with relapsed T-ALL or patients with resistant disease. Finally, there is a need to identify patients currently potentially overtreated and thus unnecessarily subjected to acute and long term toxicities without benefit. A major challenge therefore, is the identification of novel reliable prognostic markers, in order to identify patients at high risk of relapse and conversely those least likely to relapse, to guide therapy appropriately. Children predicted with a high risk of relapse would be candidates for intensification of therapy and/or novel experimental agents. Conversely, patients predicted to be at low risk of relapse could be offered clinical trials using reduced intensity therapy, thereby minimising toxicity. '...' Crucially, the 3-gene predictor was validated in a completely independent cohort of T-ALL patients, also treated on CCG style therapy. Our 3-gene predictor appears to identify a high risk group of patients which require alternative therapeutic strategies in order to attain a cure. This study has also identified a potential novel agent for the treatment of T-ALL, which may be used as an anthracycline potentiator or anthracycline-sparing agent. We hypothesised that genes associated with a relapse signature provide promising targets for novel therapies. We tested the hypothesis that CFLAR, an inhibitor of the extrinsic apoptotic pathway and a member of the 3-gene predictor may be involved in the development of resistance to chemotherapy. To test our hypothesis we used a novel agent, 2-cyano-3, 12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), previously shown to inhibit CFLAR protein, in two cell lines established in our laboratory from paediatric patients diagnosed with T-ALL. We found that CDDO displayed single agent activity at sub-micromolar concentrations in both cell lines tested. Importantly, minimally lethal doses of CDDO resulted in significant enhancement of doxorubicin mediated cytotoxicity in one of the cell lines assessed. The findings presented as part of this thesis have revealed the value of gene expression analysis of childhood T-ALL for identifying novel prognostic markers. This study has shown that expression profiles may provide better prognostic information than currently available clinical variables. Additionally, genes that constitute a relapse signature may provide rational targets for novel therapies, as demonstrated in this study, which assessed a potential novel agent for the treatment of T-ALL.

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Nordström, Marie. « Epidemiological aspects on hairy cell leukaemia / ». Linköping : Univ, 1999. http://www.bibl.liu.se/liupubl/disp/disp99/Med592s.htm.

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Hiraragi, 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.

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Thesis (Ph. D.)--Ohio State University, 2005.
Title 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

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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.

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During tumorigenesis many oncogenic pathways are reprogrammed and modulate mitochondrial metabolism, decreasing oxidative phosphorylation (OXPHOS) activity. They inhibit ATP synthesis and ROS production from OXPHOS complexes favoring metabolic switching toward a more glycolytic metabolism and tumor growth. This metabolic rewiring is well established in solid tumor but very little is known about this event in non-solid tumors such as leukemias. Indeed, it has been demonstrated that in chronic lymphocytic leukemia (B-CLL), cells show a high OXPHOS activity and elevated ROS levels. Notably, expression of the p66Shc protein, whose mitochondrial fraction modulates cell bioenergetics and increases ROS generation, is lost during B-CLL tumorigenesis. I investigate the effects of the expression of p66Shc on bioenergetics and viability of B-CLL cells. After p66Shc expression in MEC-1 cells, a B-CLL cell model, a fraction of it is in the intermembrane space of mitochondria. p66Shc expression decreases both basal and maximal respiration, decreases mitochondrial membrane potential, total ATP levels and renders cells less dependent from OXPHOS to ATP supply without changes mitochondrial mass. I propose that decreased mitochondrial respiration is due to decreased activity of respiratory complex I and II. In more detail, there is a decrease in complex I assembly with a consequent inhibition of its activity, and a decrease in complex II activity caused by a multi-protein complex in which TRAP1 and active ERK are involved. p66Shc expression in MEC-1 cells increases mitochondrial ERK activation. The mitochondrial fraction of ERK contribute to tumor cell survival by inhibiting opening of the permeability transition pore (PTP), a mitochondrial channel whose opening irreversibly commits cells to death. I check the effect of p66Shc expression on cell viability. Although its pro-apoptotic function well described in many cell models, in MEC-1 cells p66shc protects cells from death induced by mitochondrial-derived oxidative stress derived from starvation, EM20-25 and CisPlatin treatments. In depletion conditions, p66Shc expression correlates with more active mitochondrial ERK and the inhibition of ERK decreases cell viability. Inhibition of mitochondrial chaperones activity with Cyclosporine A, an inhibitor of CyP-D, or 17AAG, an inhibitor of TRAP1, also affects cell viability under depletion condition, thus supporting the hypothesis that mitochondrial ERK is involved in survival mechanism induced by p66Shc expression. Taken together these data indicate that regulation of RC complex activity can be linked to regulation of cell survival. We hypothesize that the mitochondrial branch of the Ras-ERK signaling pathway regulates mitochondrial bioenergetics by affecting SDH activity and resistance to apoptosis of B-CLL cells. Through the activation of mitochondrial ERK and inhibition of SDH activity, p66Shc can decrease OXPHOS activity and ROS production, a condition that is necessary in the early stages of tumorigenesis. It can also support tumour cell growth making mPTP less sensitive to opening by activating mitochondrial ERK.
Durante 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.

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49

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.

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Since the early twentieth century, biological responses to extracellular ATP have been documented in Virtually every major organ and tissue system. Our laboratory has focussed on the ability of extracellular ATP to induce elevations in the intracellular cAMP content of acute myelocytic leukaemia HL-60 cells, which subsequently results in their differentiation towards a more mature neutrophil-like cell type.

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Dielschneider, Rebecca. « Targeting Susceptible Signaling Pathways in Chronic Lymphocytic Leukemia ». Cell Death and Disease, 2014. http://hdl.handle.net/1993/31681.

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Chronic lymphocytic leukemia (CLL) is a cancer of B cells and is the most common leukemia in North America. Current therapies are fraught with challenges, and drug resistance and disease relapse remain common occurrences. Therefore, novel therapies and novel therapeutic strategies are needed to improve CLL therapy. Better yet, therapies targeted at specific weaknesses of CLL cells will ensure maximum efficacy and minimum adverse toxicity. To this end, this thesis focuses on targeting the susceptible BCR pathway and lysosome-mediated cell death pathway using gefitinib and lysosomotropic agents, respectively. Firstly, the novel use of the tyrosine kinase inhibitor gefitinib was explored. This drug was most effective in aggressive ZAP-70+ CLL cells and cell lines. A similar inhibitor, erlotinib, had no effect in CLL. Gefitinib inhibited phosphorylation of Syk and ZAP-70, prevented downstream kinase activation, and supressed the pro-survival BCR response. ZAP-70 is implicated in the mechanism of action of gefitinib as introduction of ZAP-70 into a B cell line increased their sensitivity to gefitinib. Secondly, the novel strategy of targeting lysosomes was explored. The lysosomotropic drugs siramesine, nortriptyline, desipramine, mefloquine, and tafenoquine were all found to induce cytotoxicity and lysosome permeabilization. Lysosome permeabilization was accompanied with lipid peroxidation and followed by loss of mitochondrial membrane potential. Compared with healthy B cells, CLL cells were more sensitive to this cell death pathway. This was potentially due to the overexpression of SPP1 and overproduction of sphingosine, which destabilized lysosomes. Lastly, this thesis explored the clinical utility of these targeted therapies. Both gefitinib and siramesine were more effective in CLL cells than patient T cells. Furthermore, they retained efficacy amid protective stromal cells. Clinical correlations revealed that gefitinib and siramesine were effective in CLL cells with poor prognostic features. Siramesine was more effective in male cells and in previously-treated cells. Gefitinib was most effective in young patients. Overall, work presented herein demonstrates the efficacy of the tyrosine kinase inhibitor gefitinib and lysosomotropic agents in primary CLL cells. This work investigates the altered biology of the BCR pathway and lysosomes in CLL cells, and takes advantage of these weaknesses using targeted therapies.
October 2016

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Thèses sur le sujet « Leukemia cell »

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