Establishing a chemical biological platform to profile E2F1 function in chronic myeloid leukaemia (CML) stem cells

Dr Glenn Burley (Chemistry, University of Strathclyde) https://www.strath.ac.uk/staff/burleyglenndr/
Dr Heather Jørgensen (Cancer Sciences, University of Glasgow)
Prof Tessa Holyoake (Cancer Sciences, University of Glasgow)

Background –There are approximately 50 new cases of Chronic Myeloid Leukaemia (CML) reported every year in Scotland. Whilst the incidence (1-2 per 100,000) is unchanging, with reducing mortality (less than 3% per year) and prolonged remissions without cure in the majority of patients treated with tyrosine kinase inhibitors, the prevalence is increasing year on year. Although current inhibitors of the oncogenic BCR-ABL kinase are initially effective, they do not kill leukaemia stem cells (LSCs) resulting in their persistence and detectable minimal residual disease. Our collaboration has identified the transcription factor E2F1 is over-expressed in LSCs and is responsible for tumourigenesis of CML. At present, there is a lack of methods available to profile the broader function of E2F1 in LSCs.

Project Objective – The principal objective of this studentship is to develop a new chemical biological platform to profile E2F1 function in LSCs. This will involve understanding the DNA-binding profile of E2F1 within genes under E2F1 control. The work will be highly inter-disciplinary involving solid phase synthesis, probe development and gene expression analysis by deep sequencing analysis.

Academic Environment – The student undertaking this project will receive unparalleled experience in all aspects of modern chemical biology within our interdisciplinary collaboration. Dr Glenn Burley has extensive experience in small molecule synthesis, bioconjugation and solid phase peptide/nucleic acid synthesis. Cell-based experiments will be conducted in the Paul O’Gorman Leukaemia Research Centre (Gartnavel Hospital) in collaboration with Dr  Heather Jørgensen and Prof. Tessa Holyoake. Dr Francesca Pellicano, Drug Discovery Unit, Beatson Institute will provide E2F1 consultancy to the project.

Keywords: Chemical biology; Transcription factor; Leukaemia; Synthetic organic chemistry; Solid phase synthesis

References:

Weldon, C.; Behm-Ansmant, I.; Hurley, L.H.; Burley, G.A.; Branlant, C.; Eperon, I.C.; Dominguez, C. Identification of G-quadruplexes in functional RNAs using FOLDeR Nat. Chem. Biol., 2016, doi:10.1038/nchembio.2228

Hatit, M.Z.C.; Sadler, J.C.; McLean, L.A.; Whitehurst, B.C.; Seath, C.P.; Humphreys, L.D.; Young, R.J.; Watson, A.J.B.; Burley, G.A. “Chemoselective Sequential Click Ligations Directed by Enhanced Reactivity of an Aromatic Ynamine” Org. Lett., 2016, 18, 1694.

Fallows, A.J.; Singh, I.; Dondi, R.; Cullis, P.M.; Burley, G.A. Highly efficient synthesis of DNA-binding polyamides using a convergent fragment-based approach. Org. Lett., 2014, 16, 4654.

Smith, L.D.; Dickinson, R.L.; Lucas,C.M.; Cousins, A.; Malygin, A.A.; Weldon, C.; Perrett, A.J.; Bottrill, A.R.; Searle, M.S.; Burley, G.A.; Eperon, I.C. A targeted oligonucleotide enhancer of SMN2 exon 7 splicing forms competing quadruplex and protein complexes in functional conditions. Cell Reports, 2014, 9, 1.

Singh, I.; Wendeln, C.; Clarke, A.W.; Cooper, J.M., Ravoo B.J.; Burley, G.A. Sequence-selective detection of double-stranded DNA sequences using pyrrole-imidazole polyamide microarrays. J. Am. Chem. Soc., 2013, 135, 3449.

I Ben-Batalla*, R Erdmann*, H.G. Jørgensen*, R Mitchell, T Ernst, G von Amsberg, P Schafhausen, S Rankin, RE Clark, S Koschmieder, A Schultze, S Mitra, P Vandenberghe, TH Brümmendorf, P Carmeliet, A Hochhaus, K Pantel, C Bokemeyer, GV Helgason, TL Holyoake and S Loges. BGB324 inhibits ABL-TKI-resistant chronic myeloid leukemia. Clin Can Res, 2016, in press {*contributed equally}

A Tarafdar, LEM Hopcroft, P Gallipolli, F Pellicano, J Cassels, A Hair, K Korfi, H.G. Jørgensen, D Vetrie, TL Holyoake, AM Michie. CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression Blood, 2016, Oct 28. pii: blood-2016-09-742049. [Epub ahead of print]

B Zhang, S Chu, P Agarwal, VL Campbell, L Hopcroft, H.G. Jørgensen, AS Lin, K Gaal, TL Holyoake, and R Bhatia. Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells. Blood, 2016, Sep 12. pii: blood-2015-11-679928. [Epub ahead of print]

MT Scott, K Korfi, P Saffrey, LEM Hopcroft, R. Kinstrie, F Pellicano, C Guenther, P Gallipoli, M Cruz, H.G. Jørgensen, JE Cassels, A Hamilton, A Crossan, A Sinclair, TL Holyoake, and D Vetrie. Global PRC2 reprogramming renders CML stem cells dependent on EZH2 and H3K27me3 for survival. Cancer Discovery, 2016, 6(11):1248-1257.

KME Laidlaw, S Berhan, S Liu, G Silvestri, TL Holyoake, DA Frank, B Aggarwal, MY Bonner, D Perrotti, H.G. Jørgensen*, J Arbiser*: Combination of the NADPH Oxidase inhibitor imipramine blue with nilotinib demonstrates activity against chronic myeloid leukemia stem cells. Oncotarget, 2016, Jul 12. doi: 10.18632/oncotarget.10541. [Epub ahead of print] {* co-corresponding author}

Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition. Scott MT, Korfi K, Saffrey P, Hopcroft LE, Kinstrie R, Pellicano F, Guenther C, Gallipoli P, Cruz M, Dunn K, Jorgensen HG, Cassels JE, Hamilton A, Crossan A, Sinclair A, Holyoake TL, Vetrie D. Cancer Discov. 2016 Nov;6(11):1248-1257.

CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression. Tarafdar A, Hopcroft LE, Gallipoli P, Pellicano F, Cassels J, Hair A, Korfi K, Jørgensen HG, Vetrie D, Holyoake TL, Michie AM. Blood. 2016 Oct 28. pii: blood-2016-09-742049. [Epub ahead of print]

Lifting the Differentiation Embargo. Latif AL, Holyoake TL. Cell. 2016 Sep 22;167(1):45-6. doi: 10.1016/j.cell.2016.08.051.

Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells. Zhang B, Chu S, Agarwal P, Campbell VL, Hopcroft L, Jørgensen HG, Lin A, Gaal K, Holyoake TL, Bhatia R. Blood. 2016 Sep 12. pii: blood-2015-11-679928. [Epub ahead of print]

Casting a NETwork instead of shooting magic bullets. Abraham SA, Holyoake TL. Cell Cycle. 2016 Aug 31:1-2. [Epub ahead of print]

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