About the Project
Our laboratory studies the mechanisms regulating normal blood stem cells and cancers such as Acute Myeloid Leukaemia (AML) and how they interact with the bone marrow microenvironment. AML is a deadly form of blood cancer, and despite advances in genome wide technology and RNA sequencing, patients diagnosed after the age of 60 usually die within a year of diagnosis. This is because AML is highly dependent on the tumour microenvironment for its survival, proliferation and chemotherapy resistance. In this PhD we will use knowledge generated from our previous work to investigate the mechanism which allow for protection of AML and normal blood stem cells in the bone marrow niche. This PhD project will combine studies of genetically modified macrophages, with mouse studies with mice and analysis of human samples with the aim of identifying cellular mechanisms that control AML survival and proliferation in the bone marrow microenvironment.
AML is primarily a disease of the elderly with three quarters of patients diagnosed after the age of 60. Increasing doses, or variations of cytotoxic chemotherapy regimens, have been trialled in recent decades but without success and accordingly it is envisaged that novel approaches to treating AML, informed by an improved scientific understanding of the disease, will be needed to improve outcomes for patients in the future.
Training for the successful PhD candidate will be provided in the areas of AML and normal blood stem cell biology, biology of macrophages and phagocytosis, advanced flow cytometry, single cell sorting as well as in mouse AML modelling. As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities.
For more information on the project’s supervisor, please visit: https://people.uea.ac.uk/s_rushworth
Type of programme: PhD
Start date of project: October 2020.
Mode of study: full time.
Studentship length: 3 years. (3 year studentships have a (non-funded) 1 year ‘registration only’ period).
Location: UEA: BCRE
Entry requirements:
a) acceptable first degree: Medicine (eg MBBS) or related Biological Sciences degree, 2:1 degree
The standard minimum entry requirement is 2:1
References
i) ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Mistry JJ, Marlein CR, Moore JA, Hellmich C, Wojtowicz EE, Smith JGW, Macaulay I, Sun Y, Morfakis A, Patterson A, Horton RH, Divekar D, Morris CJ, Haestier A, Di Palma F, Beraza N, Bowles KM, Rushworth SA. Proc Natl Acad Sci U S A. 2019 Dec 3;116(49):24610-24619
ii) Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, Piddock RE, Shafat MS, Morfakis A, Mehta T, Di Palma F, Macaulay I, Ingham CJ, Haestier A, Collins A, Campisi J, Bowles KM, Rushworth SA. Blood. 2019 Jan 31;133(5):446-456.
iii) PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts. Marlein CR, Zaitseva L, Piddock RE, Raso-Barnett L, Scott MA, Ingham CJ, Collins A, Bowles KM, Rushworth SA. Leukemia. 2018 Sep;32(9):2073-207.
iv) NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Marlein CR, Zaitseva L, Piddock RE, Robinson SD, Edwards DR, Shafat MS, Zhou Z, Lawes M, Bowles KM, Rushworth SA. Blood. 2017 Oct 5;130(14):1649-1660.
v) The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis. Rai S, Arasteh M, Jefferson M, Pearson T, Wang Y, Zhang W, Bicsak B, Divekar D, Powell PP, Naumann R, Beraza N, Carding SR, Florey O, Mayer U, Wileman T..Autophagy. 2019 Apr;15(4):599-612.
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