Grant: Project Grant

Mutations in the RUNX1 gene are involved in many diseases of the blood system. In acute myeloid leukemia (AML), the presence of RUNX1 mutations is associated with decreased survival. RUNX1 mutations are also observed in leukemia arising from hematological diseases with a predisposition to AML. No treatment specifically designed for AML with RUNX1 mutations currently exists. Our laboratory has discovered a group of drugs called glucocorticoids (GCs) that specifically kill leukemic cells carrying RUNX1 mutations as well as another drug, Lenalidomide, which potentiates the effects of GCs in AML cells. Both GCs and Lenalidomide are currently used in the treatment of other hematological diseases. Even though these results are very promising, additional studies are required to identify which patients will most likely respond to these compounds before clinicians can begin testing the effects of GCs and Lenalidomide on patients suffering from RUNX1-mutated AML. We therefore propose to provide a complete understanding of the mode of action of these compounds, as well as of the impact of a broad spectrum of gene mutations (RUNX1 and other genes) on GC and Lenalidomide sensitivity in AML. An assessment of the impact of GC treatment on otherwise normal blood cells carrying RUNX1 mutations will also be a focus of this proposal, as GC therapy could potentially serve to prevent the transformation of normal blood cells with RUNX1 mutations into cancer cells. Overall, these studies will allow clinicians to precisely determine which patients could benefit from GC and Lenalidomide treatment, with the hope of producing a tangible impact on patients suffering from blood diseases involving RUNX1 mutations.