Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series Presents:

Michael Kharas, PhD
Assistant Member
Molecular Pharmacology Program
Memorial Sloan Kettering Cancer Center

Hematopoietic malignancies result from dysregulated self-renewal pathways and an altered differentiation program. Acute myeloid leukemia (AML) is characterized by the abnormal development of blood cells in the myeloid lineage. Although many studies have focused on transcriptional regulators, activated kinases and epigenetic regulators, it is unknown how RNA binding proteins (RBPs) maintain the normal developmental program. Somatic mutations and aberrant expression of RBPs have recently emerged to be critically important in hematological malignancies. Our laboratory and others have demonstrated that MSI2 RBP expression predicts a poor prognosis and drives the aggressiveness of myeloid leukemia. We found that MSI2 enhances translation of Myc, Hoxa9 and Ikzf2 and is required for the self-renewal of MLL-AF9 transformed leukemia stem cells (LSCs). These data suggest that the RBP maintains a positive feedback look that controls the epigenetic landscape in leukemia. To determine if Ikzf2 contributes to the LSC program, we utilized mice that were depleted in Ikzf2 and found a delay in leukemogenesis that increased during serial transplantation. Ikzf2 deficient leukemic cells lost the self-renewal gene expression program and demonstrated increased differentiation. To further probe the altered MSI2 interactome, our laboratory has performed proteomics analysis of MSI2 interacting proteins followed by functional shRNA screening. Our studies suggest that the MSI2 RBP binding network is critical for LSC function and may provide novel therapeutic targets in AML.