Clesham, Katherine;
(2021)
Targeting c-MYB in Acute Myeloid Leukaemia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Acute myeloid leukaemia (AML) is an aggressive haematological cancer affecting both children and adults. Clinical outcomes continue to improve from refinement of chemotherapy, risk stratification and stem cell transplantation. However, disease relapse remains problematic and contributes to the relatively poor overall survival. The transcription factor c-MYB is recognised to play a central role in AML. Irrespective of the upstream fusion oncogene, it maintains aberrant transcriptional networks ensuring self-renewal and a block in differentiation which are essential for the leukaemia cell. This makes it an attractive and rational target in all AML subtypes. Previous work in our laboratory generated a c-MYB gene expression signature and used it to probe the Connectivity Map database. A list of candidate drugs was generated predicted to inverse the c-MYB signature in AML. This thesis studies the steroidal lactone Withaferin A (WFA), derived from Withania somnifera, a candidate ‘hit’ predicted to inhibit c-MYB in AML. We provide evidence that WFA-induced gene expression changes are consistent with a block in the c-MYB transcriptional programme in AML. WFA interfered with c-MYB function by inducing loss of c-MYB protein. WFA-induced c-MYB loss occurred across a range of AML subtypes and resulted in loss of cell viability and differentiation of leukaemia cells. Using a degradation-resistant c-MYB, we demonstrate partial rescue of WFA-induced inhibition of colony formation, indicating that c-MYB is a critical target of WFA. WFA-treated gene expression changes demonstrate enrichment in gene sets implicated in protein translation, and WFA-induced c-MYB loss was accompanied by phosphorylation of eIF2α. This implicates inhibition of protein translation as the likely cause of WFA-induced c-MYB loss. WFA led to inhibition of AML colony formation in AML cell lines and patient derived xenografts (PDX). In contrast, no significant reduction in colony formation was observed in normal haematopoietic progenitor cells. This study highlights WFA as a compound with anti-AML properties which are mediated through loss of c-MYB.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Targeting c-MYB in Acute Myeloid Leukaemia |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10133905 |
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