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Therapeutic resolution of Myelodysplastic Syndrome (MDS) by natural products


Faculty of Life Sciences

About the Project

Myelodysplastic syndromes (MDS) are a type of blood cancer where the patients do not have enough healthy blood cells. It is the most common adult myeloid malignancy in the UK and has been estimated that around 8,000 and 40,000 new cases are diagnosed each year in the UK and USA, respectively.[1] MDS are a heterogeneous group of clonal haematopoietic stem cell disorders characterized by peripheral blood cytopenias and progenitor expansion. Approximately 30% of patients will transform to secondary acute myeloid leukemia (AML) which has a poor prognosis.[2] There is no cure for MDS. Current management therapies include allogeneic haematopoietic cell transplantation, DNA methytransferase inhibitors (DNMTI), also termed hypomethylating agents (HMA), azacitidine or decitabine. Most MDS patients are not eligible for cell transplantation whilst azacitidine has been shown to modestly improve survival compared to standard care.[3] Once patients stop responding to HMA therapy, however, outcomes are dismal, with a median survival of less than six months.[4]

Using unbiased sequencing approaches, we (in collaboration with Washington University, USA) and others have identified mutations in 4 genes including SF3B1, SRSF2, U2AF1, and ZRSR2, which are involved in pre-mRNA splicing in ~50% of patients with MDS, making this cellular pathway the most commonly mutated in MDS.[5-8] Current therapies were established prior to the fact that MDS has substantial splicing abnormalities and hence there is a need to identify novel therapeutic intervention targeting the over-active spliceosomal genes.

We have developed high-throughput splicing assays [9-11] [12], screened thousands of natural products and established drugs and identified novel hits. The major objectives of this project are to (a) investigate how overactive splicing contributes to disease pathogenesis and (b) determine whether natural products may provide therapeutic intervention.

The project will introduce the student to the broader areas of molecular genetics, biochemistry, drug discovery, pharmacology and translational medicine. The research activities will be undertaken at the School of Pharmacy and Medical Sciences, University of Bradford. The studies will be performed in the recently renovated laboratories provided with state of the art equipments including high-throughput fluorescence and luminescence plate readers, QPCR machines, gel doc systems and modern tissue culture facilities. The research sits in the context of a highly active research environment at the University of Bradford.

Funding Notes

This is a self-funded project; applicants will be expected to pay their own fees or have access to suitable third-party funding, such as the Doctoral Loan from Student Finance. In addition to the university's standard tuition fees, bench fees of £5000 or £10000 per year may also apply to this project.

References

based algorithm: high number of uncaptured cases by cancer registries. Blood, 2011. 117(26): p. 7121-5.
2. Greenberg, P.L., et al., Revised international prognostic scoring system for myelodysplastic syndromes. Blood, 2012. 120(12): p. 2454-65.
3. Silverman, L.R., et al., Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol, 2002. 20(10): p. 2429-40.
4. Jabbour, E., et al., Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer, 2010. 116(16): p. 3830-4.
5. Yoshida, K., et al., Frequent pathway mutations of splicing machinery in myelodysplasia. Nature, 2011. 478(7367): p. 64-9.
6. Graubert, T.A., et al., Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet, 2011. 44(1): p. 53-7.
7. Papaemmanuil, E., et al., Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med, 2011. 365(15): p. 1384-95.
8. Visconte, V., et al., SF3B1, a splicing factor is frequently mutated in refractory anemia with ring sideroblasts. Leukemia, 2012. 26(3): p. 542-5.
9. Nasim, M.T., et al., HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding. Hum Mol Genet, 2003. 12(11): p. 1337-48.
10. Nasim, M.T., H.M. Chowdhury, and I.C. Eperon, A double reporter assay for detecting changes in the ratio of spliced and unspliced mRNA in mammalian cells. Nucleic Acids Res, 2002. 30(20): p. e109.
11. Nasim, M.T. and I.C. Eperon, A double-reporter splicing assay for determining splicing efficiency in mammalian cells. Nat Protoc, 2006. 1(2): p. 1022-8.
12. Hu, J., et al., AKAP95 regulates splicing through scaffolding RNAs and RNA processing factors. Nat Commun, 2016. 7: p. 13347.

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