Erythropoiesis

Principal Investigator: Dr Melanie Percy

Haematopoiesis is the process by which primitive stem cells proliferate and differentiate to produce mature blood cells. It is driven by highly co-ordinated patterns of gene expression under the influence of growth factors and hormones. Dysregulated gene expression is the causative factor in many haematological disorders and detailed knowledge of the regulation of gene expression is central to the understanding of the mechanisms that cause anaemia, leukaemia and other blood disorders.

Most patients who suffer from cancer are also anaemic. Erythropoietin(EPO),a glycoprotein hormone produced in the kidney is the primary inducer of red cell production. Although EPO circulates only at picomolar levels in the plasma it effectively regulates red cell production by the bone marrow. In cancer and certain chronic diseases EPO production is blunted but inflammatory cytokines are increased. These two factors retard red blood cell production. Fortunately recombinant human EPO has been developed for treating anaemia in end-stage renal disease and is now used increasingly to treat patients with cancer. The response to EPO varies from patient to patient and further work is required to elucidate the specific pathogenic mechanisms underlying the onset and progression of the anaemia.

We are investigating EP0-induced gene expression during terminal differentiation of human and murine erythroid cells. Using the technique of differential display PCR (DD-PCR) we have identified a group of fourteen genes regulated by EPO which match uncharacterised ESTs. Current efforts are focused on the characterisatian of one of these gene designated ERIC- I,for erythropoietin-induced cDNA. ERIC-I is expressed in the spleen and bone marrow and the highest levels are found in the testes.

The EPO receptor spans the membrane of developing erythroid cells. The extracellular domain responds to circulating EPO and the intracellular domain contains a C-terminal regulatory region that acts as a brake on red cell production. A mutation in the receptor DNA that causes truncation of the inhibitory region is enough to produce an obvious increase in the number of red cells. This type of mutation was first found in Finland, in the family of an Olympic cross-country skiing gold medalist who has a "natural" advantage: a gene that allows his blood to carry more oxygen. All affected members of the family are descended from one couple born in the 1850's. Our group has identified a similar mutation in an unrelated English boy, and is currently investigating the molecular basis of other myoloproliferative disorders.

Erythopoiesis Team

Post-doctoral Scientists:	Dr Vivien Hodges	Dr Zhanzhong Shi
Post-graduate Students:	Victoria Kyle (with Prof Ken Mills)	Marie Gaines (with Prof. Terry Lappin)