12 Jun 2021 Research

First Medical Research Council and Leukaemia UK Clinical Research Training Fellow shares project highlights

Dr Sandeep Potluri’s findings will contribute towards a better understanding, cure and treatments of leukaemia and blood cancers.

Leukaemia UK works jointly with the Medical Research Council to fund clinical research training fellowships, to offer clinical professionals the opportunity to launch novel research projects combining clinical care and biological research. Ultimately, with the goal of translating new discoveries relating to leukaemia and blood cancer into standard practice and treatments.

Dr Sandeep Potluri was the inaugural Medical Research Council and Leukaemia UK Clinical Research Training Fellow. He completed his medical degree at the University of Cambridge and studied for his PhD at the University of Birmingham, where his Fellowship was also awarded. He now works as a Specialist Registrar in Haematology, looking after patients with haematological cancers and other haematological conditions.

As his research project recently came to an end in February 2021, he shares his progress and explains how the findings will contribute towards a better understanding of, cure and treatments for leukaemia and blood cancers.

The overarching aim of his Dr Potluri’s project was to understand Gene Regulatory Networks in acute myeloid leukaemia (AML) and to help identify potential therapeutic targets. Patients with AML have an unacceptably poor prognosis and have broadly been treated with the same intensive chemotherapy since the 1970s. It is only in the last few years that more targeted therapies have emerged.

New therapeutic options

The Wilms Tumour 1 (WT1) gene is overexpressed or mutated in both AML cells and in stem cells from which the cancer originates. Early trials using T Cell Receptors against WT1 in patients in remission have shown that this prevents relapse, but the mechanism was unclear. Dr Potluri’s team’s findings showed mechanistically how WT1 confers a leukaemic phenotype by binding to specific genomic regions, altering gene expression and altering intracellular signalling.

Importantly, their studies demonstrated that only some isoforms of WT1 confer leukaemic behaviour to the cell whilst other isoforms inhibit leukaemic behaviour; this has implications on future drug design.

Whilst the focus of the project was on WT1, they also constructed Gene Regulatory Networks by performing gene expression and chromatin accessibility experiments on leukaemia cells derived from patients treated locally in Birmingham. This highlighted several potential therapeutic vulnerabilities such as t(8;21) AML being sensitive to the cell cycle inhibitor, Palbociclib, which is already used in patients with breast cancer. This may lead to new therapeutic options.

‘Therapies against WT1 are emerging which were demonstrated to prevent relapse in AML patients. We have provided much of the mechanistic background to why therapies targeting WT1 would work and provided the most in-depth understanding about this transcription factor in AML, to date’

Impact of the research

Acute myeloid leukaemia is an aggressive haematological malignancy and five-year survival rates, when all age groups are taken into account, remains staggeringly low at just 15.3%. Patients often undergo intensive chemotherapy and allogeneic transplantation, which in themselves confer significant Treatment-Related Mortality rates. Unfortunately, even those patients who achieve clinical remission frequently develop relapsed disease.

Dr Potluri’s research has led to a greater understanding of AML and demonstrates further progress in the search for new targeted, more effective and kinder treatments. In particular, investigations into alterations of levels of WT1 highlighted a role for WT1 in the maintenance of leukaemia cells but had no effect on healthy blood stem cells. Dr Potluri has highlighted WT1 as an attractive therapeutic target and a potential future treatment option for AML.

I am extremely?grateful for the support and to all the fundraisers who have raised money to support this research

Several publications have arisen through this project and Dr Potluri had a first author paper published in Cell Reports on a further potential target, Wilms Tumour 1 (WT1), as well as co-authorships on papers published in Nature Genetics about AML-specific transcription factor networks and in Cancer Cell on therapeutic vulnerabilities in t(8;21) AML.

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