Grant: Operating Grant

Many patients with blood cancer die despite intensive chemotherapy. One particular subtype of blood cancer is called T-cell Acute lymphoblastic leukemia and is one the most common forms of cancer in children. Leukemia usually arises, when the genetic system controlling normal blood forming cells in the bone marrow is not working properly and these cells become cancer cells. This cancer cells then multiply in an uncontrolled manner, enter the bloodstream and cause leukemia with the consequence that the function of the red blood cells (oxygen transport) and the white blood cells (immune defense) are compromised leading to a severe illness and death. Different causes have been described for leukemia, one is the malfunction of a protein called Notch1 caused by a mutation in the Notch1 gene. We have observed that another regulatory protein called Gfi1 can influence the function of Notch1 and we found that if we turn the Gfi1 gene off in a mouse, the mutated form of Notch is no longer able to cause leukemia in this animal. Moreover, if the Gfi1 gene is turned off in a mouse that already has leukemia, the cancer shrinks and disappears. In addition we have also found that if the Gfi1 gene is not completely switched off but just turned down the development of leukemia in our mouse models is markedly accelerated. We conclude that blood cancer cells need the Gfi1 gene and without Gfi1 they cannot proliferate and cause the leukemia, but rather regress and die off. However, we must also conclude that cancer cells develop fastest into a very aggressive form when they have reduced Gfi1 gene activity. In the present study, We wish to investigate the mechanisms that are responsible for these functions of Gfi1 in more detail. The result of this work would enable us to design a therapy, which would involve the elimination of Gfi1 in cancer cells with the final objective to improve therapy in leukemia patients