Prof P Vyas
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
AML is the most common aggressive human leukaemia with a poor outcome. There is an urgent need for new therapies to improve survival. AML is an excellent model to study cancer stem cells. AML is hierarchically organised, compromised of a pool of leukaemia propagating stem cells (LSCs) with sustained self renewal capacity that differentiate into more mature leukaemic cells. To cure patients therapies will have eradicate LSC populations. Over the last 8 years the Vyas laboratory has been purifying LSC populations from a large number of primary human AML samples[1, 2]. The Vyas lab has established RNA-Seq profiles from a large number of different genetic types of primary human AML and 9 highly purified normal human stem/progenitor and precursor populations. Comparisons of these profiles shows that AML LSCs are arrested at either progenitor or precursor stages of differentiation. These profiles also establish that AML LSCs express a very limited gene set of key normal stem cell transcription factors, chromatin regulators and signalling molecules important in driving self-renewal and leading to differentiation arrest.
In the project the candidate will focus on specific stem cell regulators expressed in AML LSCs. First, the candidate will generate lentiviral libraries of either shRNA or CAS9/CRISPR guides to knock out specific groups of regulators in AML cell lines and primary human LSCs both in vitro[3] and in vivo.The candidate will work closely with the WIMM genome engineering core and lentiviral viral production facility in the design of libraries and screens.
This will provide a platform to test the cis- and trans-acting mechanisms, including the epigenetic processes, that lead abrreant self renewal and differentiation arrest in AML LSCs. This work will involve molecular and biochemical approaches including ATAC-Seq, profiling histone marks, methy-DNA marks and mechanistic studies of the proteins required for sustained transcription.
For further information contact Professor Paresh Vyas [Email Address Removed].
Funding Notes
Funding for this project is available to basic scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2017 entry, the application deadline is 6th January 2017 at 12 noon (midday).
Please visit our website for more information on how to apply.
References
1. Goardon, N., et al., Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. Cancer Cell, 2011. 19(1): p. 138-52.
2. Quek L, Otto GW, et al (2016) Functional and genetic heterogeneity of distinctive leukemic stem cell populations in CD34- human acute myeloid leukaemia. JEM 213:1513-1535 (2016).
3. Pabst, C., et al., Identification of small molecules that support human leukemia stem cell activity ex vivo. Nat Methods, 2014. 11(4): p. 436-42.
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