Grant: Operating Grant

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults, yet it has the lowest survival rate with less than 30% of adult patients reaching complete remission. Even patients achieving pathologic complete remission after chemotherapy and bone-marrow transplant will almost invariably relapse if post-remission therapy is not administered. The major cause of the resistance to therapy is thought to be leukemic stem cells, which are present in small amounts compared to other malignant cells but are incredibly resistant to current treatments. Targeted therapies aiming at destroying specifically leukemic stem cells as opposed to current treatments that destroy all dividing cells are required to 1) achieve a better survival rate and 2) to diminish the secondary effects of current AML treatments. We have recently identified a protein called Hemogen, which regulates the expression of genes in blood cells. Interestingly, this protein is aberrantly expressed in AML patients and its level of expression at diagnosis is inversely correlated to a favorable response to chemotherapy. Preliminary results have indicated that forced expression of Hemogen induces leukemia in mice, while removal of the Hemogen protein from cells of AML patients leads to a decrease in proliferation. All these results strongly suggest that Hemogen has an important role in initiating and maintaining leukemia in patients. In this project, we propose to use cellular and molecular approaches to identify the genes and the proteins that work with Hemogen to induce and maintain leukemia. In addition, we will remove the Hemogen protein from AML blasts and determine the extent to which this could ameliorate the disease. These experiments are expected to reveal the role of Hemogen in the formation and the maintenance of the leukemic cells. As such, our studies are expected to identify new candidate molecular targets that could be used as a therapy to eradicate leukemic cells.