Genomics, Diagnosis, Novel Targeted Therapies and Characterisation of the Drivers of Relapse in Philadelphia Chromosome-Like Acute Lymphoblastic Leukaemia
type: CreativeWork
description: This thesis focuses on Philadelphia chromosome-like (BCR::ABL1-like) acute lymphoblastic leukaemia (Ph-like ALL), a subtype of B-cell ALL recently recognised as a distinct entity. The genomic drivers of Ph-like ALL are diverse. This thesis emphasises investigation of the JAK/STAT class of lesions. Ph-like ALL patients continue to have poor prognosis, in contrast to patients with other subtypes of B-ALL such as Philadelphia chromosome positive ALL, who have had significant improvements in outcomes with targeted therapies. A significant obstacle in Ph-like ALL has been imprecise case-by-case characterisation of the genomic landscape, which is especially relevant for lesions which have not yet been shown to be actionable by precision inhibitors. This thesis hypothesised that fluorescence in-situ hybridisation (FISH) would be an accurate, efficient and practical method for diagnosis of Ph-like ALL genomic lesions in the real-world. Based on current literature, it was postulated that a diagnostic algorithm could be developed by using FISH as a single initial investigation to identify relevant lesions. The dismal prognosis of JAK/STAT activated ALL demands new therapeutic approaches. In vitro models of JAK rearrangements have been limited by instability of relevant murine cell lines in culture, and an improved culture technique was developed using Ba/F3 cell lines to define a reliable model for testing relevant therapeutic agents against cell lines transfected with JAK fusions. The model was tested against standard responses previously published for the JAK2 inhibitor ruxolitinib, authenticating methods for determining lethal dose 50 (LD50). It was demonstrated that combination inhibitors would be more effective against JAK fusions known to confer particularly poor prognosis. In an in vitro model, proteosome inhibitors carfilzomib and bortezomib were combined with ruxolitinib and demonstrated potency and, for carfilzomib, synergy against the commonest JAK fusion, PAX5::JA…
abstract: This thesis focuses on Philadelphia chromosome-like (BCR::ABL1-like) acute lymphoblastic leukaemia (Ph-like ALL), a subtype of B-cell ALL recently recognised as a distinct entity. The genomic drivers of Ph-like ALL are diverse. This thesis emphasises investigation of the JAK/STAT class of lesions. Ph-like ALL patients continue to have poor prognosis, in contrast to patients with other subtypes of B-ALL such as Philadelphia chromosome positive ALL, who have had significant improvements in outcomes with targeted therapies. A significant obstacle in Ph-like ALL has been imprecise case-by-case characterisation of the genomic landscape, which is especially relevant for lesions which have not yet been shown to be actionable by precision inhibitors. This thesis hypothesised that fluorescence in-situ hybridisation (FISH) would be an accurate, efficient and practical method for diagnosis of Ph-like ALL genomic lesions in the real-world. Based on current literature, it was postulated that a diagnostic algorithm could be developed by using FISH as a single initial investigation to identify relevant lesions. The dismal prognosis of JAK/STAT activated ALL demands new therapeutic approaches. In vitro models of JAK rearrangements have been limited by instability of relevant murine cell lines in culture, and an improved culture technique was developed using Ba/F3 cell lines to define a reliable model for testing relevant therapeutic agents against cell lines transfected with JAK fusions. The model was tested against standard responses previously published for the JAK2 inhibitor ruxolitinib, authenticating methods for determining lethal dose 50 (LD50). It was demonstrated that combination inhibitors would be more effective against JAK fusions known to confer particularly poor prognosis. In an in vitro model, proteosome inhibitors carfilzomib and bortezomib were combined with ruxolitinib and demonstrated potency and, for carfilzomib, synergy against the commonest JAK fusion, PAX5::JA…
author: Thompson, Jane Frances
language: en
keywords: acute lymphoblastic leukaemia, Ph-like, genomics
date published: 2025
date modified: 2026-07-24T00:51:05Z
provider: University of Adelaide
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Adelaide

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property ID: Handle
value: https://hdl.handle.net/2440/146514