Grant: Project Grant

Acute leukemia are still the leading cause of death by cancer before the age of 40. Acute myeloid leukemia (AML) have only a 50% cure rate in children and less than 10% in > 65 year old patients. Improvements at all levels, from basic science to patient care, are needed to improve these bad numbers. AML is a genetically heterogeneous disease with recurrent translocations and mutations that arise in stem/progenitors cells leading to the clinical disease. A better understanding of the biology of the different AML can lead to better therapy and outcome. This approach has been successful for acute promyelocytic leukemia (APL) which had a very poor outcome before the development of ATRA and arsenic trioxide, two molecules that induce the differentiation of APL cells. Their combination now cures more than 90% of this subtype of AML. Our team has recently studied the role of S100A8 and S100A9 proteins in AML. We found that S100A8 maintains the undifferentiated state of leukemic cells while S100A9 can induce their differentiation through the cell surface receptor TLR4. We showed that a small population of leukemic cells expresses the S100A8/A9 proteins and we suspect these cells are responsible for the maintenance of the leukemia which can also be called leukemic stem cells. Using murine models of leukemia, we showed that treatment with the S100A9 protein or an anti-S100A8 antibody prolonged the survival of the mice through differentiation of leukemic cells. In the current proposal, we aim to better characterize the cells expressing S100A8/A9 proteins and determine if they are leukemic stem cells. We will also better understand the effects of the proteins, their receptors and their cellular pathways. Finally, we will test our proteins and antibodies in vivo on both human AML models and on patient samples in mice. These studies are essential to move towards the clinical application of differentiation therapy in AML using our new tools.