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Understanding the role of HoxA9 in chemotherapy resistance of Acute Myeloid Leukaemia (AML)

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Acute Myeloid Leukaemia (AML) is a rare but yet deadly form of blood cancer. Genome-wide expression arrays and RNA sequencing have contributed to unravelling the leukaemia signature genes. Expression of a single gene, HOXA9, has been identified as the single most critical prognostic factor for a subgroup of AML patients characterised by chromosomal translocations involving the Mixed Lineage Leukaemia gene (MLL also known as KMT2A). Despite our growing knowledge, there is no targeted therapeutic approach currently available to patients affected by MLL-driven leukaemia, which represents the most highly aggressive and chemo-refractory form of AML.

HOXA9 is a homeobox gene expressed during embryonal haematopoiesis and silenced in adulthood. Expression of HOXA9 confers resistance to chemotherapy and leads to a rapidly developing leukaemia in mice. HOXA9 as well as other homeobox genes are not oncogenes but they have been found over-expressed in several solid cancers, including glioma and prostate cancer; the expression of these genes correlates with poor prognosis indicating an important contribution of these genes in the aggressiveness of these tumours. HOXA9 knock down sensitize leukemic cells to chemotherapy, although the underlying mechanisms are still unknown. Understanding this mechanism is important to design appropriate novel targeted therapeutics for this incurable disease and to understand how homeobox genes contribute to chemotherapy resistance. We recently showed for the first time that expression of HOXA9 confers, to otherwise sensitive leukemic cells, resistance to DNA damage repair inhibitors (Poly-ADP ribose polymerase inhibitors, PARPi) via activation of DNA damage repair (Esposito, Zhao et al. Nature Medicine 2015). This PhD project will continue this research and will investigate the effect of HoxA9 on molecular mechanisms of chemotherapy resistance, in particular on DNA damage repair and cell cycle progression, with the aim to design novel therapeutic approaches.

The successful applicant will be given training in all aspects of the project and will be encouraged to develop as a motivated and independent researcher by benefitting from the knowledge, experience and the multidisciplinary focus of the Health Science Research Center of the University of Roehampton.

Funding Notes

Dr Maria Teresa Esposito is a John Goldman fellow and is currently funded by Leuka and the British Society of Hematology.

References

1. Esposito, M. T. The impact of PI3-Kinase/RAS pathway cooperating mutations in the evolution of KMT2A- rearranged leukemia. Hemasphere in press (2019).

2. Esposito MT, Zhao L, Fung TK, Rane JK, Wilson A, Martine N, Gil J, Ashworth A, So CW. “Synthetic lethal targeting of oncogenic transcription factors in acute leukaemia using PARP inhibitors” Nature Medicine 2015 Dec 21 (12): 1481-90

3. Esposito MT and Chi Wai Eric So “DNA damage accumulation and repair defects in the pathogenesis of Acute Myeloid Leukaemia: implications for pathogenesis, disease progression and chemotherapy resistance.” Chromosoma 2014 Dec 123(6):545-61

How good is research at University of Roehampton in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 10.00

Research output data provided by the Research Excellence Framework (REF)

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