Elucidating the mechanisms of leukemogenesis driven by FBXO11 depletion
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Mo, Ya-Chi Angela
issued: 2023-06-30T07:00:00Z
issued: 2022
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: We examined the AML-PMP, TCGA, TARGET pediatric, and Beat AML public datasets to identify genetic drivers of AML. We identified frequent somatic mutations in ubiquitin proteasome system genes, with recurrent inactivating mutations in FBXO11. FBXO11 encodes the substrate-recognizing component of the SKP1-CUL1-F-BOX (SCF) ubiquitin E3-ligase complex. In a mouse marrow transplant model generated by previous members of the Karsan lab, Fbxo11 knockdown cooperated with AML1-ETO expression to initiate AML. These leukemias were serially transplantable, consistent with the presence of leukemic stem cells (LSC). We hypothesized that FBXO11 depletion in hematopoietic stem and progenitor cells (HSPC) promotes self-renewal and drives leukemogenesis through dysregulated expression of its ubiquitination targets. First, we developed a serially transplantable human xenotransplant myeloid leukemia model based on FBXO11 depletion with cooperating mutations, and observed increased engraftment and expansion of primitive CD34⁺ cells with FBXO11 knockdown. Next, to identify FBXO11 targets that are dysregulated with FBXO11 depletion, we performed mass spectrometry analysis of FBXO11 co-immunoprecipitating proteins in the myeloid K562 cell line. We identified LONP1 as a top target, but LONP1 protein expression did not change with FBXO11 over-expression or loss, suggesting that LONP1 is not targeted for degradation. Knockdown of LONP1 in human CD34⁺ HSPCs resulted in similar phenotypes as FBXO11 knockdown: enriched hematopoietic stem cell, LSC, and mitochondrial defect transcriptomic signatures, increased myeloid cells, and reduced erythroid and megakaryocytic populations. In parallel, FBXO11 knockdown reduced mitochondrial membrane potential. These data suggest that FBXO11 normally positively regulates LONP1. We found that K63-linked polyubiquitination—a modification known to regulate protein activation and trafficking— of LONP1 is increased with FBXO11 overexpression, and reduced with FBXO…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/81723
note: 南無本師大自在王佛 ELUCIDATING THE MECHANISMS OF LEUKEMOGENESIS DRIVEN BY FBXO11 DEPLETION by Ya-Chi Angela Mo B.Sc., University of British Columbia, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Pathology and Laboratory Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) June 2022 ©Ya-Chi Angela Mo, 2022 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Elucidating the Mechanisms of Leukemogenesis Driven by FBXO11 Depletion Submitted by _Ya-Chi Angela Mo in partial fulfillment of the requirements for the degree of _Doctor of Philosophy in _Pathology and Laboratory Medicine Examining Committee: Dr. Aly Karsan, Professor, Pathology and Laboratory Medicine, UBC ______ Supervisor Dr. Andrew Weng, Professor, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Dr. Fabio Rossi, Professor, Medical Genetics, UBC_____________________ University Examiner Dr. Kirk Schultz, Professor, Pathology and Laboratory Medicine, UBC______ University Examiner Additional Supervisory Committee Members: Dr. Peter Stirling, Associate Professor, Medical Genetics, UBC Supervisory Committee Member Dr. Thibault Mayor, Professor, Biochemistry and Molecular Biology, UBC Supervisory Committee Member iii Abstract We examined the AML-PMP, TCGA, TARGET pediatric, and Beat AML public datasets to identify genetic drivers of AML. We identified frequent somatic mutations in ubiquitin proteasome system genes, with recurrent inactivating mutations in FBXO11. FBXO11 encodes the substrate-recognizing component of the SKP1-CUL1-F-BOX (SCF) ubiquitin E3-ligase complex. In a mouse marrow transplant model generated by previous members of the Karsan lab, Fbxo11 knockdown cooperated with AML1-ETO expression to initiate AML. These leukemias were serially transplantable, consisten…
has type: Thesis/Dissertation
date issued: 2022-11
is shown at: 10.14288/1.0413788
language: eng
degree discipline: Pathology and Laboratory 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
contributor: Karsan, Aly
type: Text
identifier URI: http://hdl.handle.net/2429/81723