Abstract LB-256: Targeting MLL1 methyltransferase activity for treatment of acute leukemia with MLL1 rearrangement

Abstract

Abstract Translocation of the MLL1 gene, which encodes for the histone methyltransferase, MLL1, is found in approximately 10% of all cases of acute leukemia and is generally associated with poor patient outcomes. Recent research has pointed to an essential function for the wild-type copy of MLL1 in these leukemias. In these cells, abnormal upregulation of MLL1-directed histone methylation and subsequent overexpression of MLL1 gene targets is an essential step in the development and progression of leukemia. Efficient MLL1-catalyzed histone methylation can only be achieved when MLL1 associates with the complex of WDR5, RbBP5 and Ash2L. MLL1 complex assembly is nucleated by a highly conserved interaction between the MLL1 SET domain and WDR5. We hypothesize that blocking histone methyltransferase activity of wild-type MLL1 through inhibition of the essential WDR5-MLL1 interaction will prevent abnormal gene upregulation and transformation in leukemias with MLL1 rearrangement. Using rational design, we have developed potent inhibitors for WDR5. We have demonstrated that the lead compound, MM-401, can disrupt the interaction of MLL1 with WDR5, and prevent assembly of the MLL1 complex. We have also shown that MM-401 specifically inhibits MLL1 complex activity, with an IC50=320nM. Using MLL1 fusion-transduced mouse bone marrow cells as a model, we have shown that treating leukemia cells with MM-401 inhibits expression of the MLL1 target oncogene, HoxA9, in a concentration-dependent fashion. Treatment of these cells with MM-401 also promotes differentiation of leukemia blasts in a dose dependent manner. Furthermore, MM-401 specifically impairs cell growth and viability of human leukemia cell lines with MLL1 rearrangement but does not alter growth of leukemia cell lines with mutations or translocations targeting other oncogenes. In conclusion, we have developed a potent inhibitor MM-401, which is the first in a novel class of inhibitors designed to target MLL1 methyltransferase activity, one of the most important chromatin modifying enzymes for transcription activation. We have further demonstrated that pharmacological inhibition of the MLL1 methyltransferase activity specifically targets leukemias with MLL1 rearrangement, and shifts leukemia cells away from the undifferentiated, rapidly proliferating state that is characteristic of aggressive AMLs. These results point to a promising new therapeutic target for leukemia treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-256. doi:1538-7445.AM2012-LB-256