Inhibition of the DNA Damage Response as a Targeted Therapy in Myeloproliferative Neoplasms.

Myeloproliferative neoplasms (MPNs) occur when patients acquire genetic ‘driver mutations’ (commonly in JAK2 or CALR) in haematopoietic stem cells (HSCs) causing aberrant blood cell production resulting in thrombosis, splenomegaly, bone marrow fibrosis and leukaemia. These reduce quality-of-life and shorten lifespan.
A goal for MPN treatment is targeting HSCs with driver mutations whilst sparing healthy HSCs, restoring normal haematopoiesis. We propose drugs inhibiting the DDR will do this. HSCs with driver mutations have a heightened DDR compared to healthy HSCs. We hypothesise that inhibiting the DDR will cause catastrophic DNA damage and cell death specifically in HSCs with MPN driver mutations, whereas healthy HSCs will recover and survive. This will be examined through two objectives:

Objective 1: Determine the effect of combinations of DDR inhibitors on DNA damage, cell proliferation and cell death in the presence of wild-type and mutant JAK2 and CALR in a cell line model.

Objective 2: Using optimal drug combinations identified above, determine effects in primary cells from MPN patients with JAK2 and CALR mutations, comparing wild-type and mutant cells within each patient.

Lead Academic at Lead Institution

Dr Sally Thomas – University of Sheffield

Lead Academics at other Institutions

Professor Ian Hitchcock – University of York
Dr Edwin Chen – University of Leeds

Other people associated with this project

Sheffield:

  • Dr Helen Bryant 
  • Dr Andrew Chantry
  • Dr Martin Zeidler 

York: Dr Dimitris Lagos

Leeds: Dr Maria Gilleece  -Leeds Teaching Hospitals.