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postgraduate thesis: Mechanism of homoharringtonine sensitizing venetoclax in acute myeloid leukaemia
Title | Mechanism of homoharringtonine sensitizing venetoclax in acute myeloid leukaemia |
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Authors | |
Advisors | |
Issue Date | 2023 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Kwok, T. H. [郭子豪]. (2023). Mechanism of homoharringtonine sensitizing venetoclax in acute myeloid leukaemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature myeloid cells in bone marrow or peripheral blood. It is a heterogeneous disease with different genetic and cytogenic abnormalities. Standard treatments such as chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) have reached an impasse and the treatment outcomes were usually unsatisfactory. An alternative treatment strategy for AML is urgently needed. Recently, multiple studies showed that targeting the apoptosis pathway by inhibiting antiapoptotic protein B cell lymphoma 2 protein (BCL-2) was effective, especially in those patients who are unfit for intensive treatment.
Venetoclax, a BH3 mimic specific to BCL-2, is an FDA-approved drug used in combination with a hypomethylating agent (HMA) and low dose cytarabine (LDAC) for AML. Although the combination of venetoclax with HMA and LDAC showed a promising effect in some patients, some AML subtypes such as TP53 mutant AML showed de novo resistance to the treatment and the mechanism was unknown. In this study, we showed that homoharringtonine (HHT), a protein translation inhibitor, synergized with venetoclax in suppressing the growth of AML both in vitro and in vivo. This observation supported that HHT combined with venetoclax is an effective regime in AML with de novo resistance to venetoclax. We further investigated the mechanism of the sensitization of venetoclax by HHT. Since HHT inhibits protein translation, we have performed a proteomics analysis studying the dynamics of newly synthesized proteins (NSPs) after HHT treatment. In total, 27 NSPs were effectively downregulated by HHT treatment in venetoclax-resistant AML cell lines. By performing a CRISPR-Cas9 dropout screen of the 27 NSPs in a venetoclax-resistant AML cell line, knockout of IRX3 and CD1D sensitized venetoclax efficacy in AML. The results showed that HHT might sensitize venetoclax by suppressing the protein expression of IRX3 and CD1D in de novo venetoclax-resistant AML.
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Degree | Master of Philosophy |
Subject | Acute myeloid leukemia - Treatment Alkaloids - Therapeutic use Antineoplastic agents |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/332199 |
DC Field | Value | Language |
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dc.contributor.advisor | Man, CH | - |
dc.contributor.advisor | Leung, AYH | - |
dc.contributor.author | Kwok, Tsz Ho | - |
dc.contributor.author | 郭子豪 | - |
dc.date.accessioned | 2023-10-04T04:54:42Z | - |
dc.date.available | 2023-10-04T04:54:42Z | - |
dc.date.issued | 2023 | - |
dc.identifier.citation | Kwok, T. H. [郭子豪]. (2023). Mechanism of homoharringtonine sensitizing venetoclax in acute myeloid leukaemia. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/332199 | - |
dc.description.abstract | Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of immature myeloid cells in bone marrow or peripheral blood. It is a heterogeneous disease with different genetic and cytogenic abnormalities. Standard treatments such as chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) have reached an impasse and the treatment outcomes were usually unsatisfactory. An alternative treatment strategy for AML is urgently needed. Recently, multiple studies showed that targeting the apoptosis pathway by inhibiting antiapoptotic protein B cell lymphoma 2 protein (BCL-2) was effective, especially in those patients who are unfit for intensive treatment. Venetoclax, a BH3 mimic specific to BCL-2, is an FDA-approved drug used in combination with a hypomethylating agent (HMA) and low dose cytarabine (LDAC) for AML. Although the combination of venetoclax with HMA and LDAC showed a promising effect in some patients, some AML subtypes such as TP53 mutant AML showed de novo resistance to the treatment and the mechanism was unknown. In this study, we showed that homoharringtonine (HHT), a protein translation inhibitor, synergized with venetoclax in suppressing the growth of AML both in vitro and in vivo. This observation supported that HHT combined with venetoclax is an effective regime in AML with de novo resistance to venetoclax. We further investigated the mechanism of the sensitization of venetoclax by HHT. Since HHT inhibits protein translation, we have performed a proteomics analysis studying the dynamics of newly synthesized proteins (NSPs) after HHT treatment. In total, 27 NSPs were effectively downregulated by HHT treatment in venetoclax-resistant AML cell lines. By performing a CRISPR-Cas9 dropout screen of the 27 NSPs in a venetoclax-resistant AML cell line, knockout of IRX3 and CD1D sensitized venetoclax efficacy in AML. The results showed that HHT might sensitize venetoclax by suppressing the protein expression of IRX3 and CD1D in de novo venetoclax-resistant AML. | - |
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 - Treatment | - |
dc.subject.lcsh | Alkaloids - Therapeutic use | - |
dc.subject.lcsh | Antineoplastic agents | - |
dc.title | Mechanism of homoharringtonine sensitizing venetoclax in acute myeloid leukaemia | - |
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 | 2023 | - |
dc.identifier.mmsid | 991044723910703414 | - |