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Identifying novel therapeutic targets in CMML


   Faculty of Biology, Medicine and Health


About the Project

Chronic myelomonocytic leukaemia (CMML) is a clonal stem cell neoplasm defined by abnormal monocytosis and dysplasia. A quarter of CMML patients progress to acute myeloid leukaemia and these patients have dismal prognosis. Allogeneic haematopoietic stem cell transplantation is the only curative option for CMML, although advanced age and lack of suitable donors preclude many patients being considered for this therapy. There are few other treatment options for CMML patients and these are limited in significant part due to the poor understanding of the underlying mechanisms that drive disease progression. Identifying new therapeutic strategies will require a deeper understanding of disease initiation, sustenance and progression. In depth molecular analysis on disease initiating stem cell and disease propagating monocytes from CMML patients and healthy controls identified several potential therapeutic targets. The prospective student will investigate: 1) the effect of targeting the aberrantly expressed factors on CMML cell survival; 2) the molecular mechanism involved cell survival mediated by these factors; and 3) upstream pathways responsible for the aberrant expression in CMML patient samples. Data from this study will be used to establish therapeutic targets against CMML cells.

Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who have, or are expected to obtain a first or upper second class honours degree and who are highly committed to pursuing a PhD in cancer research.

Entry Requirements

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience, particularly in cell culture and molecular biology, are particularly encouraged to apply.

How To Apply

For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Genetics

For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/”

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk


Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Wiseman DH, Baker SM, Dongre AV, Gurashi K, Storer JA, Somervaille TC, Batta K. Chronic myelomonocytic leukaemia stem cell transcriptomes anticipate disease morphology and outcome. EBioMedicine 58, 102904 (2020).

Yoshimi A *, Lin K*, Wiseman D *, Rahman M, Pastore A, Wang W, Lee S , Micol J, Zhang XJ, Botton S, Lacronique VP, Stein E, Cho H , Miles R, Inoue D, Albecht T , Somervaille TCP, Batta K, Amaral F, Simeoni F, Wilks D, Cargo C, Intlekofer A, Levine R, Dvinge H, Bradley R, Wagner E , Krainer A, Omar Abdel-Wahab. Coordinated Alterations in RNA Splicing and Epigenetic Regulation Drive Leukemogenesis. Nature , 574(7777); 273-277 *Equal contribution

Hurtado AM, Luengo-Gil G, Chen-Liang TH, Amaral F, Batta K, Palomo L, et al. Transcriptomic rationale for synthetic lethality-targeting ERCC1 and CDKN1A in chronic myelomonocytic leukaemia. British Journal of Haematology. 2018; 182(3); 373-383

MS Williams, FMR Amaral, F Simeoni and TCP Somervaille (2019). Dynamic induction of drug resistance through a stress responsive enhancer in acute myeloid leukaemia. Journal of Clinical Investigation (2020); 130(3) 1217-1232.

G Deb, B Wingelhofer, FMR Amaral, A Maiques-Diaz, EL William, HS Leong, T Maes and TCP Somervaille (2019). Combined LSD1 and mTORC1 inhibition induces enhanced differentiation in MLL-translocated acute myeloid leukaemia. Leukemia. 34(5) 1266-1277.

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