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postgraduate thesis: Investigating the role of TP53 in acute myeloid leukaemia (AML) using the zebrafish model
Title | Investigating the role of TP53 in acute myeloid leukaemia (AML) using the zebrafish model |
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Authors | |
Advisors | |
Issue Date | 2020 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Kan, L. L. H. [簡禮鶴]. (2020). Investigating the role of TP53 in acute myeloid leukaemia (AML) using the zebrafish model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | This project focuses on the cooperativity of TP53 and other proliferative signal gene mutations (FLT3-ITD, NRAS G12D) in acute myeloid leukaemia (AML). p53 is a well-characterized transcription factor that plays a major role in cell cycle regulation, DNA repair, apoptosis, and growth signalling. In solid cancers, TP53 mutations occur in 50% of cases. In AML, TP53 mutations occur almost exclusively in a subtype with complex / monosomy karyotype (CK/MK). Non-mutational p53 abnormalities may also play a pathogenetic role in leukaemogenesis. AML with perturbation of p53 functions respond poorly to conventional chemotherapy and are associated with high relapse risk. In addition, cumulative studies suggested that pathogenetic functions of specific mutations in myeloid malignancies might depend on co-existing mutations, demonstrating cooperativity or mutual exclusivity. There is an unmet clinical need to identify novel therapeutic strategies for this disease and improve treatment outcomes.
In this study, I investigated the effects of perturbing tp53 in both adult zebrafish and embryos on haematopoiesis. Potential cooperativity with oncogenes including FLT3-ITD and NRAS G12D was also examined. The results showed that while overexpression of FLT3-ITD and NRAS G12D could induce myeloid expansion in the embryonic model, concomitant knockdown of tp53 did not exacerbate the phenotype. On the other hand, stable transgenic line of FLT3-ITD and tp53 mutant exhibited potential cooperativity, as evidenced by the expansion of myeloid precursor populations in adult kidney marrow.
In conclusion, this study made use of zebrafish embryos and adult fish and demonstrated potential cooperativity between recurrent AML mutations (FLT3-ITD and NRAS G12D) with tp53 mutation, Cooperativity was only observed in adult fish, supporting the proposition that additional insults (e.g. accumulating DNA damage or ROS levels) acquired during adulthood are needed to induce leukaemogenesis. |
Degree | Master of Philosophy |
Subject | Acute myeloid leukemia - Animal models |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/283108 |
DC Field | Value | Language |
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dc.contributor.advisor | Leung, AYH | - |
dc.contributor.advisor | Ng, RK | - |
dc.contributor.author | Kan, Leo Lai Hok | - |
dc.contributor.author | 簡禮鶴 | - |
dc.date.accessioned | 2020-06-10T01:02:11Z | - |
dc.date.available | 2020-06-10T01:02:11Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Kan, L. L. H. [簡禮鶴]. (2020). Investigating the role of TP53 in acute myeloid leukaemia (AML) using the zebrafish model. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/283108 | - |
dc.description.abstract | This project focuses on the cooperativity of TP53 and other proliferative signal gene mutations (FLT3-ITD, NRAS G12D) in acute myeloid leukaemia (AML). p53 is a well-characterized transcription factor that plays a major role in cell cycle regulation, DNA repair, apoptosis, and growth signalling. In solid cancers, TP53 mutations occur in 50% of cases. In AML, TP53 mutations occur almost exclusively in a subtype with complex / monosomy karyotype (CK/MK). Non-mutational p53 abnormalities may also play a pathogenetic role in leukaemogenesis. AML with perturbation of p53 functions respond poorly to conventional chemotherapy and are associated with high relapse risk. In addition, cumulative studies suggested that pathogenetic functions of specific mutations in myeloid malignancies might depend on co-existing mutations, demonstrating cooperativity or mutual exclusivity. There is an unmet clinical need to identify novel therapeutic strategies for this disease and improve treatment outcomes. In this study, I investigated the effects of perturbing tp53 in both adult zebrafish and embryos on haematopoiesis. Potential cooperativity with oncogenes including FLT3-ITD and NRAS G12D was also examined. The results showed that while overexpression of FLT3-ITD and NRAS G12D could induce myeloid expansion in the embryonic model, concomitant knockdown of tp53 did not exacerbate the phenotype. On the other hand, stable transgenic line of FLT3-ITD and tp53 mutant exhibited potential cooperativity, as evidenced by the expansion of myeloid precursor populations in adult kidney marrow. In conclusion, this study made use of zebrafish embryos and adult fish and demonstrated potential cooperativity between recurrent AML mutations (FLT3-ITD and NRAS G12D) with tp53 mutation, Cooperativity was only observed in adult fish, supporting the proposition that additional insults (e.g. accumulating DNA damage or ROS levels) acquired during adulthood are needed to induce leukaemogenesis. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Acute myeloid leukemia - Animal models | - |
dc.title | Investigating the role of TP53 in acute myeloid leukaemia (AML) using the zebrafish model | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Master of Philosophy | - |
dc.description.thesislevel | Master | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2020 | - |
dc.identifier.mmsid | 991044242095303414 | - |