Acute myeloid leukemia (AML) is a devastating disease with poor survival. The standard treatments of chemotherapy and/or stem cell transplantation are not specific, and are toxic to blood cells, resulting in severe treatment-related complications for patients. Leukemias are composed of rapidly dividing “blast” cells, and the more rare “leukemic stem cells” (LSCs). These LSCs can lead to resistance and relapse, because they can evade chemotherapy. To achieve long-term remissions in AML and prevent relapse, we need to find more specific ways to kill LSCs.
The enzyme PI3 kinase (PI3K), which can modify proteins inside the cell, is more active in leukemic cells than in normal cells. However, PI3K is also important in normal blood cells. We identified a strategy to specifically kill leukemic cells by blocking specific components of PI3K called “isoforms”, which can sometimes substitute for each other in normal blood cells. We will determine whether this therapeutic strategy can also be used to kill LSCs.
Leukemic cells can also evade chemotherapy by hiding in their bone marrow microenvironment, the “niche”. Niche cells and leukemic cells “talk” to each other by sending signals back and forth, which can protect leukemic cells from chemotherapy. Cells need PI3K to process such signals. Inhibition of PI3K in niche cells could potentially kill leukemic cells by short-circuiting this crosstalk with the niche. We have found that PI3K in the niche cells is important for blood development. We will now examine whether inhibition of PI3K in the niche can compromise leukemic growth and progression.
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