The role of FBXO11 in human hematopoiesis
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Wang, Xuan
issued: 2022-07-31T07:00:00Z
issued: 2020
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Acute myeloid leukemia (AML) is an aggressive blood disease associated with complex mutational patterns. Our previous AML sequencing study has revealed frequent somatic mutations in ubiquitin proteasome system (UPS) genes, with recurrent loss-of-function mutations in FBXO11, which codes substrate-recognition component for E3 ubiquitin ligase complex. Our mouse transplant model shows a biological cooperation between Fbxo11 knockdown and enforced AML1-ETO expression in driving mouse leukemogenesis. However, to-date the role of FBXO11 depletion in contributing to human leukemogenesis remains unclear. Gene set enrichment analysis (GSEA) on microarray data of FBXO11-knockdown human hematopoietic stem and progenitor cells (HSPCs) revealed a significant enrichment in stem cell signature, and dysregulated pathways centered on hypoxia and delay in cell cycle progression. Our work further shows that FBXO11 loss confers quiescence while enhancing more primitive populations ex vivo. Co-occurrence and exclusivity of UPS gene mutations with other frequent variants in AML were previously computed and reveal a significantly strong trend of RAS mutations co-occurring with UPS mutations in leukemogenesis. Given that FBXO11 knockdown confers quiescence on human HSPCs ex vivo and AML emerges as a heterogeneous disease with complex co-mutation patterns, we investigated in parallel the effect of KRASG12D (K) and AML1-ETO (A) alone and in combination with FBXO11 knockdown, to examine whether FBXO11 depletion can cooperate with leukemia-associated oncogenes to initiate AML in a xenograft model. Our results show that FBXO11 depletion restrains the growth of KA cells ex vivo, possibly through delaying Gâ exit, while enhancing their in vivo repopulating capacity, potentially leading to leukemogenesis.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/75256
note: THE ROLE OF FBXO11 IN HUMAN HEMATOPOIESIS by Xuan Wang B.Sc., University of Victoria, 2018 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2020 ©Xuan Wang, 2020 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, a thesis entitled: The role of FBXO11 in human hematopoiesis submitted by Xuan Wang in partial fulfillment of the requirements for the degree of Master of Science In Experimental medicine Examining Committee: Dr. Aly Karsan, Professor, Department of Pathology, UBC Supervisor Dr. Andrew Weng, Professor, Department of Pathology, UBC Supervisory Committee Member Dr. Florian Kuchenbauer, Associate Professor, Department of Medicine, UBC Supervisory Committee Member Dr. Edward Conway, Professor, Department of Medicine, UBC Additional Examiner iii Abstract Acute myeloid leukemia (AML) is an aggressive blood disease associated with complex mutational patterns. Our previous AML sequencing study has revealed frequent somatic mutations in ubiquitin proteasome system (UPS) genes, with recurrent loss-of-function mutations in FBXO11, which codes substrate-recognition component for E3 ubiquitin ligase complex. Our mouse transplant model shows a biological cooperation between Fbxo11 knockdown and enforced AML1-ETO expression in driving mouse leukemogenesis. However, to-date the role of FBXO11 depletion in contributing to human leukemogenesis remains unclear. Gene set enrichment analysis (GSEA) on microarray data of FBXO11-knockdown human hematopoietic stem and progenitor cells (HSPCs) revealed a significant enrichment in stem cell signature, and dysregulated pathways centered on hypoxia and delay in cell cycle progression. Our work further shows that FBXO11 loss confers quiescence while enhancing more primitive…
has type: Thesis/Dissertation
date issued: 2020-11
is shown at: 10.14288/1.0392529
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/75256