Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)

The prognosis for relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is very poor, emphasizing the critical need to identify the underlying molecular mechanisms and targeted treatments. In this study, we delved into the molecular factors driving therapeutic resistance in DLBCL by conducti...

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Main Author: Peng, Chenchen
Other Authors: Li Yinghui
Format: Thesis-Doctor of Philosophy
Language:English
Published: Nanyang Technological University 2024
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Online Access:https://hdl.handle.net/10356/174839
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spelling sg-ntu-dr.10356-1748392024-05-03T02:58:53Z Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL) Peng, Chenchen Li Yinghui School of Biological Sciences liyh@ntu.edu.sg Medicine, Health and Life Sciences The prognosis for relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is very poor, emphasizing the critical need to identify the underlying molecular mechanisms and targeted treatments. In this study, we delved into the molecular factors driving therapeutic resistance in DLBCL by conducting transcriptome and epigenome profiling across multiple cellular models of intrinsic and acquired chemoresistance. This study established DLBCL cell line models that mirror primary and acquired doxorubicin (DOX) resistance observed in DLBCL patients, facilitating our investigation. Firstly, we found that DOX-resistant cells exhibit unique gene expression patterns, enriched in metabolic processes and Wnt signaling, compared to DOX-sensitive cells. Furthermore, doxorubicin-induced resistant-specific upregulated genes can partially predict pan-cancer doxorubicin sensitivity and partially overlap with genes linked to acquired doxorubicin-resistant DLBCL cells. Next, we demonstrated that the non-canonical NF-κB pathway plays a pivotal role in activating genes associated with crucial biological processes contributing to doxorubicin resistance, revealing potential predictive biomarkers and therapeutic targets. Subsequently, we investigated the mechanism responsible for acquired doxorubicin resistance in DLBCL, alongside insights into epigenetic dysregulation in acquired DOX resistance. The activation of the MAPK and JAK-STAT pathways and their association with immune responses were identified in DLBCL DOX resistance. The pathway-associated TFs JunD and STAT2 contributed to DOX resistance. Furthermore, chromatin accessibility and enhancer landscape showed genome-wide changes, as well as JunD and STAT2 binding profiles during the acquired DOX resistance. These epigenetic alterations showed a positive correlation in this context. This revealed potential predictive biomarkers and therapeutic targets of JunD and STAT2 and their regulated genes. Collectively, this research unveils intricate mechanisms orchestrating doxorubicin resistance in DLBCL, spanning transcriptomic and epigenetic aspects. The findings provide potential signaling pathways and associated molecular factors for predictive biomarkers and therapeutic interventions to combat DLBCL treatment resistance. By offering comprehensive insights into DLBCL resistance, this study contributes to the foundation of innovative approaches aimed at enhancing patient outcomes. As more research emerges, the study's implications hold promise for improved therapeutic strategies against this challenging malignancy. Doctor of Philosophy 2024-04-15T04:10:24Z 2024-04-15T04:10:24Z 2023 Thesis-Doctor of Philosophy Peng, C. (2023). Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL). Doctoral thesis, Nanyang Technological University, Singapore. https://hdl.handle.net/10356/174839 https://hdl.handle.net/10356/174839 10.32657/10356/174839 en This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0). application/pdf Nanyang Technological University
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
spellingShingle Medicine, Health and Life Sciences
Peng, Chenchen
Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
description The prognosis for relapsed and refractory diffuse large B-cell lymphoma (DLBCL) is very poor, emphasizing the critical need to identify the underlying molecular mechanisms and targeted treatments. In this study, we delved into the molecular factors driving therapeutic resistance in DLBCL by conducting transcriptome and epigenome profiling across multiple cellular models of intrinsic and acquired chemoresistance. This study established DLBCL cell line models that mirror primary and acquired doxorubicin (DOX) resistance observed in DLBCL patients, facilitating our investigation. Firstly, we found that DOX-resistant cells exhibit unique gene expression patterns, enriched in metabolic processes and Wnt signaling, compared to DOX-sensitive cells. Furthermore, doxorubicin-induced resistant-specific upregulated genes can partially predict pan-cancer doxorubicin sensitivity and partially overlap with genes linked to acquired doxorubicin-resistant DLBCL cells. Next, we demonstrated that the non-canonical NF-κB pathway plays a pivotal role in activating genes associated with crucial biological processes contributing to doxorubicin resistance, revealing potential predictive biomarkers and therapeutic targets. Subsequently, we investigated the mechanism responsible for acquired doxorubicin resistance in DLBCL, alongside insights into epigenetic dysregulation in acquired DOX resistance. The activation of the MAPK and JAK-STAT pathways and their association with immune responses were identified in DLBCL DOX resistance. The pathway-associated TFs JunD and STAT2 contributed to DOX resistance. Furthermore, chromatin accessibility and enhancer landscape showed genome-wide changes, as well as JunD and STAT2 binding profiles during the acquired DOX resistance. These epigenetic alterations showed a positive correlation in this context. This revealed potential predictive biomarkers and therapeutic targets of JunD and STAT2 and their regulated genes. Collectively, this research unveils intricate mechanisms orchestrating doxorubicin resistance in DLBCL, spanning transcriptomic and epigenetic aspects. The findings provide potential signaling pathways and associated molecular factors for predictive biomarkers and therapeutic interventions to combat DLBCL treatment resistance. By offering comprehensive insights into DLBCL resistance, this study contributes to the foundation of innovative approaches aimed at enhancing patient outcomes. As more research emerges, the study's implications hold promise for improved therapeutic strategies against this challenging malignancy.
author2 Li Yinghui
author_facet Li Yinghui
Peng, Chenchen
format Thesis-Doctor of Philosophy
author Peng, Chenchen
author_sort Peng, Chenchen
title Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
title_short Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
title_full Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
title_fullStr Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
title_full_unstemmed Identification of molecular factors mediating therapeutic resistance in diffuse large B-cell lymphoma (DLBCL)
title_sort identification of molecular factors mediating therapeutic resistance in diffuse large b-cell lymphoma (dlbcl)
publisher Nanyang Technological University
publishDate 2024
url https://hdl.handle.net/10356/174839
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