Identification of early and late transformation events in adult T cell leukaemia/lymphoma
File(s)
Author(s)
Wolf, Sonia Nadia
Type
Thesis
Abstract
Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that occurs in around 5% of carriers of the human T cell leukaemia virus type 1 (HTLV-1). Identifying the carriers at an early stage has been difficult and current methods, such as use of proviral load (PVL), lack specificity. In this thesis, a flow-cytometry based approach, using T-cell receptor subunit quantification to identify dominant clones and to calculate an oligoclonality index (OCI), was able to identify carriers with a five-fold increased risk of transformation compared to high proviral load alone. ATL driver mutations can be present many years prior to disease in subjects who subsequently transform. In order to identify whether low frequency mutations associated with oncogenesis were also present in
HTLV-1 carriers with high OCI and unknown outcomes, samples were subsequently flow-sorted into populations representing dominant clones, infected polyclonal cells and Other CD4+ cells. Eight out of nine high-OCI subjects (89%) had a mutation detected in a gene frequently mutated in ATL, at a variant allele fraction of greater than 0.1, compared to no subject with a low-OCI. Three subjects had a mutation in a dominant clone in the TCR/NFκB pathway; all three of these subjects subsequently transformed to ATL. Differential expression analysis demonstrated similarity between dominant clones and previous patterns of gene expression seen in ATL, that were distinct from differential expression seen in Infected Polyclonal cell populations. There were some patterns of gene expression unique to clones with mutations in the TCR/NFκB pathway, which may represent late change. In this work, I have demonstrated that High-OCI HTLV-1 carriers have mutational and transcriptional profiles resembling those seen in ATL, and these may reflect differing stages of transformation. These differences could be exploited for therapeutic gain and earlier treatment of HTLV-1 carriers at the highest risk of transformation.
HTLV-1 carriers with high OCI and unknown outcomes, samples were subsequently flow-sorted into populations representing dominant clones, infected polyclonal cells and Other CD4+ cells. Eight out of nine high-OCI subjects (89%) had a mutation detected in a gene frequently mutated in ATL, at a variant allele fraction of greater than 0.1, compared to no subject with a low-OCI. Three subjects had a mutation in a dominant clone in the TCR/NFκB pathway; all three of these subjects subsequently transformed to ATL. Differential expression analysis demonstrated similarity between dominant clones and previous patterns of gene expression seen in ATL, that were distinct from differential expression seen in Infected Polyclonal cell populations. There were some patterns of gene expression unique to clones with mutations in the TCR/NFκB pathway, which may represent late change. In this work, I have demonstrated that High-OCI HTLV-1 carriers have mutational and transcriptional profiles resembling those seen in ATL, and these may reflect differing stages of transformation. These differences could be exploited for therapeutic gain and earlier treatment of HTLV-1 carriers at the highest risk of transformation.
Version
Open Access
Date Issued
2022-03
Date Awarded
2022-06
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Taylor, Graham
Cook, Lucy
Rowan, Aileen
Sponsor
Medical Research Council (Great Britain)
Leukaemia UK
Grant Number
P71737
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)