Abstract IA5: Chromosomal translocations and transcriptional elongation control in epigenetics and cancer

Abstract

Abstract Chromosomal translocations involving the mixed lineage leukemia (MLL) gene occur frequently in human acute leukemia of myeloid and lymphoid lineages [1]. Many years ago, we identified the Saccharomyces cerevisiae Set1 as a MLL homologue, purified Set1/COMPASS as the first histone H3 lysine 4 (H3K4) methylase, and demonstrated that the COMPASS family and its role in H3K4 methylation is highly conserved across the evolutionary tree [1]. Recent catalogues of somatic mutations in both hematological malignancies and solid tumors have identified a large number of mutations in the components of COMPASS. Our recent studies on the importance of the COMPASS family members and histone H3K4 methylation in development and cancer pathogenesis will be discussed. Regarding MLL's translocation role in leukemic pathogenesis, there are a large number of translocation partners of MLL with little sequence or seemingly functional similarities, yet their translocations to MLL result in the pathogenesis of hematological malignancies. Approximately 16 years ago, we identified ELL, a partner of MLL in leukemia, as an RNA polymerase II (Pol II) elongation factor. On the basis of our biochemical observations regarding ELL's role, we proposed that the regulation of the rate of transcription elongation by Pol II could have a central role in leukemic pathogenesis. Biochemical studies from our laboratory have recently demonstrated that indeed many of the MLL translocation partners in addition to P-TEFb are found within a biochemically distinct protein complex, the ELL-containing Super Elongation Complex (SEC) [2, 3]. We have demonstrated that it is the translocation of MLL into SEC that is involved in the misrecruitment of SEC to MLL target genes, perturbing transcriptional elongation checkpoint control (TECC) at these loci and resulting in leukemic pathogenesis [2]. Our recent finding on the role of TECC in the regulation of gene expression during development [4] and cancer pathogenesis [5] will be discussed. 1. Shilatifard, A., The COMPASS Family of Histone H3K4 Methylases: Mechanisms of Regulation in Development and Disease Pathogenesis Annual Review of Biochemistry, 2012. 2. Lin, C., et al., AFF4, a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras can link transcription elongation to leukemia. Molecular Cell, 2010. 37(3): p. 429-37. 3. Lin, C., et al., Dynamic transcriptional events in embryonic stem cells mediated by the super elongation complex (SEC). Genes Dev, 2011. 25(14): p. 1486-98. 4. Lin, C., et al., The RNA Pol II Elongation Factor Ell3 Marks Enhancers in ES Cells and Primes Future Gene Activation. Cell, 2013 in press 5. Luo, Z., Lin, C., and Shilatifard, A., The super elongation complex (SEC) family in transcriptional control. Nature Reviews. Molecular Cell Biology, 2012. 13(9): p. 543-7. Citation Format: Ali Shilatifard. Chromosomal translocations and transcriptional elongation control in epigenetics and cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA5.