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postgraduate thesis: Potential therapeutic targets of arsenic trioxide in diffuse large B-cell lymphoma

TitlePotential therapeutic targets of arsenic trioxide in diffuse large B-cell lymphoma
Authors
Advisors
Issue Date2018
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Yue, L. [庾樂民]. (2018). Potential therapeutic targets of arsenic trioxide in diffuse large B-cell lymphoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractArsenic trioxide (ATO) is a standard therapeutic agent for acute promyelocytic leukaemia (APL). APL cells are sensitive to ATO, with ATO directly targeting the PML-RARα protein that plays an important role in the oncogenesis of APL. ATO also targets various oncogenic proteins for degradation through the ubiquitin-proteasome pathway in haematological malignancies, including cyclin D1 in mantle cell lymphoma, NPMc+ in acute myeloid leukaemia and NPM-ALK in anaplastic large cell lymphoma, thereby inducing apoptotic cell death. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma throughout the world. This study aims at identifying novel molecular targets of ATO in DLBCL, thereby expanding the therapeutic use of ATO in this malignancy. B-cell lymphoma 6 (BCL6) over-expression is frequently observed in DLBCL, either in germinal centre B-cell (GCB) or activated B-cell (ABC) sub-types. In the first part of this study, BCL6 was identified as a novel target of ATO in DLBCL. ATO inhibited cell growth and induced apoptosis significantly in BCL6-dependent DLBCL cell lines. In contrast, BCL6-independent DLBCL cell lines were less sensitive to ATO treatment. ATO degraded BCL6 protein through the ubiquitin-proteasomal pathway in both BCL6-dependent and BCL6-independent DLBCL cell lines. ATO-induced BCL6 protein degradation led to de-repression of BCL6 downstream target genes in BCL6-dependent DLBCL cells. Most importantly, the in vivo anti-lymphoma efficacy of ATO in BCL6-dependent DLBCL was also demonstrated in this study. ATO also synergized with cisplatin to reduce cell viability and induce apoptosis significantly in BCL6-dependent DLBCL cell lines through DNA damage. ALK+ DLBCL is a rare, aggressive lymphoma with a poor response to conventional therapies as comparing with typical DLBCL. The most common chimeric protein found in this type of lymphoma is CLTC-ALK. In the second part of this study, the effect of ATO on this CLTC-ALK fusion protein was studied. ATO treatment resulted in downregulation of the protein level but not mRNA level of CLTC-ALK. The proteasomal inhibitor, MG132, abolished ATO-induced CLTC-ALK protein downregulation, suggesting that ATO targeted CLTC-ALK protein for proteasomal degradation. Moreover, downstream signalling pathways of this kinase were also suppressed by ATO. ATO was also shown to inhibit cell growth and induce cell death in this cell line. In conclusion, ATO has been shown to be a potentially novel therapeutic approach for BCL6-dependent DLBCL by targeting BCL6. Accordingly, new combination therapies can be developed to expand the therapeutic spectrum of ATO to other neoplasms based on suppressing the BCL6 level. Moreover, CLTC-ALK has also been shown as an attractive therapeutic target for ATO and the use of ATO as a therapeutic agent may improve the therapeutic efficiency in treating ALK+ DLBCL, which shows poor response to conventional therapies.
DegreeDoctor of Philosophy
SubjectTherapeutic use - Arsenic compounds
Lymphomas - Treatment
Dept/ProgramMedicine
Persistent Identifierhttp://hdl.handle.net/10722/269861

 

DC FieldValueLanguage
dc.contributor.advisorKwong, YL-
dc.contributor.advisorTse, EWC-
dc.contributor.authorYue, Lok-man-
dc.contributor.author庾樂民-
dc.date.accessioned2019-05-07T01:50:55Z-
dc.date.available2019-05-07T01:50:55Z-
dc.date.issued2018-
dc.identifier.citationYue, L. [庾樂民]. (2018). Potential therapeutic targets of arsenic trioxide in diffuse large B-cell lymphoma. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/269861-
dc.description.abstractArsenic trioxide (ATO) is a standard therapeutic agent for acute promyelocytic leukaemia (APL). APL cells are sensitive to ATO, with ATO directly targeting the PML-RARα protein that plays an important role in the oncogenesis of APL. ATO also targets various oncogenic proteins for degradation through the ubiquitin-proteasome pathway in haematological malignancies, including cyclin D1 in mantle cell lymphoma, NPMc+ in acute myeloid leukaemia and NPM-ALK in anaplastic large cell lymphoma, thereby inducing apoptotic cell death. Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma throughout the world. This study aims at identifying novel molecular targets of ATO in DLBCL, thereby expanding the therapeutic use of ATO in this malignancy. B-cell lymphoma 6 (BCL6) over-expression is frequently observed in DLBCL, either in germinal centre B-cell (GCB) or activated B-cell (ABC) sub-types. In the first part of this study, BCL6 was identified as a novel target of ATO in DLBCL. ATO inhibited cell growth and induced apoptosis significantly in BCL6-dependent DLBCL cell lines. In contrast, BCL6-independent DLBCL cell lines were less sensitive to ATO treatment. ATO degraded BCL6 protein through the ubiquitin-proteasomal pathway in both BCL6-dependent and BCL6-independent DLBCL cell lines. ATO-induced BCL6 protein degradation led to de-repression of BCL6 downstream target genes in BCL6-dependent DLBCL cells. Most importantly, the in vivo anti-lymphoma efficacy of ATO in BCL6-dependent DLBCL was also demonstrated in this study. ATO also synergized with cisplatin to reduce cell viability and induce apoptosis significantly in BCL6-dependent DLBCL cell lines through DNA damage. ALK+ DLBCL is a rare, aggressive lymphoma with a poor response to conventional therapies as comparing with typical DLBCL. The most common chimeric protein found in this type of lymphoma is CLTC-ALK. In the second part of this study, the effect of ATO on this CLTC-ALK fusion protein was studied. ATO treatment resulted in downregulation of the protein level but not mRNA level of CLTC-ALK. The proteasomal inhibitor, MG132, abolished ATO-induced CLTC-ALK protein downregulation, suggesting that ATO targeted CLTC-ALK protein for proteasomal degradation. Moreover, downstream signalling pathways of this kinase were also suppressed by ATO. ATO was also shown to inhibit cell growth and induce cell death in this cell line. In conclusion, ATO has been shown to be a potentially novel therapeutic approach for BCL6-dependent DLBCL by targeting BCL6. Accordingly, new combination therapies can be developed to expand the therapeutic spectrum of ATO to other neoplasms based on suppressing the BCL6 level. Moreover, CLTC-ALK has also been shown as an attractive therapeutic target for ATO and the use of ATO as a therapeutic agent may improve the therapeutic efficiency in treating ALK+ DLBCL, which shows poor response to conventional therapies.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshTherapeutic use - Arsenic compounds-
dc.subject.lcshLymphomas - Treatment-
dc.titlePotential therapeutic targets of arsenic trioxide in diffuse large B-cell lymphoma-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineMedicine-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2018-
dc.identifier.mmsid991044040572503414-

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