|開催日時：||2017年10月19日 １６：００ 〜 １７：００|
|講師：||Scott A. Armstrong|
|所属：||Dana Farber Cancer Institute, Harvard Medical School・Professor, Pediatrics|
|演題：||Targeting Epigenetic Mechanisms in Leukemia|
Leukemia is frequently driven by mutations in genes encoding proteins that control chromatin regulatory processes and therefore maintain appropriate gene expression during hematopoietic development. Mutation of these genes promotes inappropriate expression of stem cell and self-renewal associated programs in multiple hematopoietic cell types leading to unregulated self-renewal and leukemia cell proliferation and survival. Recent studies have heightened our understanding of the details of the mechanisms how chromatin regulatory processes control inappropriate leukemia gene expression and these mechanisms are now being targeted therapeutically. Proteins such as DOT1L, BRD4, ENL and others play critical roles in the maintenance of leukemia gene expression including the gene expression programs that control stem cell-like functions and self-renewal in leukemia cells. A set of genes that are central to leukemia cell proliferation are the stem cell associated HOXA cluster genes and MEIS1. Critical histone modifications that maintain HOXA and MEIS1 expression include H3K4 methylation, H3K79 methylation, and H3K9 acetylation. The enzymes that catalyze these modifications include members of the MLL complex, DOT1L, and super elongation complex (SEC). Loss-of-function mouse models as well as small molecule inhibitors demonstrate that leukemias driven by MLL-translocations and other leukemias with high level HOX gene expression are dependent on DOT1L, the MLL complex and the SEC for proliferation and for the maintenance of HOXA and other leukemia associated gene expression. These discoveries have established a foundation for disease-specific therapies that target chromatin modifications in leukemias harboring specific genetic abnormalities. They also suggest that targeting chromatin regulatory mechanisms may allow the development of small molecule approaches to reverse inappropriate gene expression that is critical for the maintenance, proliferation and self-renewal of leukemia stem cells. Recent mechanistic, pre-clinical and clinical studies will be discussed.
中西 真 （癌防御シグナル分野）