Deregulation of Ras Signaling in MLL-Induced Leukemia

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DESCRIPTION (provided by applicant): The objective of this 5-year proposal is to provide the applicant with an integrated research training and mentoring program that will ensure her successful development as an independent physician scientist. We propose to investigate the mechanisms and develop model systems of transformation by a subset of mixed lineage leukemia (MLL) oncoproteins that may share dual roles to simultaneously activate Ras signaling and MLL transcriptional pathways. The histone methyltransferase MLL is a transcriptional regulator essential for embryonal hematopoiesis, and is frequently fused to various partner proteins in infant and secondary leukemia. The transforming ability of MLL fusion proteins is thought to be caused by aberrant transcriptional effector properties conferred by the fusion partner, but the exact mechanisms are poorly understood. We have identified the Ras association 1 domain of the MLL fusion partner AF6 as critical for activation of the oncogenic properties of MLL linking MLL-induced leukemogenesis to Ras. Also, it was recently found that due to fusion with MLL, cytoplasmic EEN and its interaction partner EEN binding protein (EBP) are abducted to the nucleus. As a result EBP no longer exerts its inhibitory function on the Ras pathway. Similarly, fusion of RASGAP to MLL results in sequestration of RASGAP in the nucleus and interferes with its ability to inhibit Ras. We hypothesize that transformation by MLL-AF6, MLL-EEN and MLL-RASGAP is in part mediated by activation of Ras and that inhibition of the Ras pathway is a suitable treatment approach for leukemias induced by these MLL-fusion proteins. To test this hypothesis, we propose the following specific aims. 1. Investigate the molecular mechanisms by which fusion with AF6, RASGAP and EEN activate the oncogenic potential of MLL. 2. Assess potential deregulation of the Ras pathway by the respective MLL fusion protein and investigate the effect of Ras pathway inhibition on their transforming ability in vitro. 3a) Establish a murine xenograft of MLL-AF6, MLL-EEN and MLL-RASGAP-induced leukemia using human cord blood cells transduced with the respective MLL fusion protein. 3b) Assess the efficacy of Ras-pathway inhibitors in the xenograft model for treatment of leukemia induced by MLL-AF6, MLL-EEN and MLL-RASGAP. These studies will lead to a better understanding of the molecular mechanisms of leukemogenesis mediated by a subset of MLL fusion proteins and may facilitate the development and testing of novel targeted therapies.