In recent years, targeting translational regulation is recognized as a promising therapeutic strategy for cancer treatment. RNA regulating proteins (RRPs) i.e. RNA binding proteins (RBPs) and associating proteins are master regulators of RNA biogenesis, which could play a major role in controlling the gene expression programs. Despite their relevant function in normal development and diseases, only a handful of RRPs have been studied in cancer. In addition, the molecular mechanism for how RRPs contribute to translational regulation and cancer progression remains poorly understood. AML is a genetically complex and heterogeneous set of diseases characterized by abnormal development of blood cells in the myeloid lineage. Despite an increased understanding of the molecular basis of AML pathogenesis, the overall survival of adult AML patients has only improved modestly in the past 30 years. Understanding how RNA regulating proteins control leukemia progression may result in the identification of novel targets. Our recent studies identified RBP SYNCRIP to be required for survival of leukemia cells. Importantly, we showed that SYNCRIP selectively controls translation of several critical regulators of leukemia stem cells e.g. HOXA9. Given the essential requirement of SYNCRIP and its function in protein synthesis, I will utilize SYNCRIP as the model to investigate the role of translational regulation mediated by RNA regulating proteins in leukemia and delineate the leukemia translational program. This proposal utilizes novel animal models and emerging technologies to comprehensively study SYNCRIP?s function and will identify new regulators of protein synthesis in leukemia. My career goal is to become an independent investigator in a major biomedical research university studying mechanisms of posttranscriptional and translational regulation in pathogenesis of myeloid leukemia to develop novel therapeutic approaches targeting these regulatory pathways. To prepare for my independent career, the goals for the training period are to: 1) acquire expertise in genetic mouse models; 2) acquire technical skills to perform genome wide approaches and 3) expand my skills on computational analysis of next generation sequencing data. I will also continue my professional development in preparation for transitioning into the independence phase. To help me with my training, I have assembled an outstanding mentoring team. Dr. Michael Kharas (MSKCC) is the primary mentor supporting my research and training in mouse models. Dr. Samie Jaffrey (Cornell Medicine) serves as co-mentor and provides training in genome wide approaches. I will also receive guidance from my Scientific Advisory Committee, which consists of outstanding scientists: Dr. Scott Lowe (MSKCC), Dr. Ari Melnick (Cornell Medicine), Dr. Andrea Ventura (MSKCC) and Dr. Omar AbdelWahab (MSKCC). Memorial Sloan Kettering Cancer Center (MSKCC) is a fertile environment for research and training with unparalleled resources for laboratory research, excellent opportunities for career development and a collaborative scientific environment. !
Abnormal translation has emerged to play a critical role in cancer. The proposed work will contribute to advance our understanding of how translational regulation mediated by RNA regulating proteins drive malignant gene expression programs in cancer. The findings from this study will form a solid scientific foundation for development of innovative therapies targeting these pathways in leukemia and other types of cancers.