Haemopoietic lineage commitment - novel regulators. [ 2007 - 2009 ]

Research Grant

Researchers: Prof Peter Klinken (Principal investigator) ,  Dr Louise Winteringham ,  Dr Stephan Morris ,  Prof Charles Bond

Brief description Haemopoiesis is the process by which cells in the blood become committed to a specific cell type, mature and proliferate. The production of blood cells is a dynamic and constant process and if dysregulated will result in a number of different diseases and-or leukemias. Using a leukemic cell line we identified two genes, Hls5 and Hls7-Mlf1, involved in red blood cell maturation. In addition, both these genes have been implicated in cancer, Hls5 functions as a tumor suppressor and Mlf1 is associated with acute myeloid leukemia. Over-expression of either gene in immature red blood cells inhibited their development; Mlf1 had quite a profound affect on cell shape and size whereas Hls5 affected biochemical pathways with a decrease in haemoglobin production. We have identified binding partners of each of the molecules. Hls5 binds to FOG 1, a regulator of the red blood cell genes. In addition, Hls5 associates with Ubc9 and PIAS-1 - molecules involved in a novel form of gene regulation called sumoylation. Hls5 also regulates GATA-1 a key protein in red cell production. Wer have recently found that Mlf1 also regulates GATA-1. Importantly, we have demonstrated that Mlf1 binds DNA and other nuclear proteins and is able to affect gene transcription. This project will use cellular and biochemical assays as well as mouse models to elucidate the mechanisms by which these genes control the function of red blood cells.

Funding Amount $AUD 584,446.74

Funding Scheme NHMRC Project Grants

Notes Standard Project Grant