主   题：Which pro-survival BCL-2 family member should be targeted for the treatment of which cancer?

　　主讲人：Andreas Strasser,Ph.D.澳大利亚科学院院士

　　时   间：2014年10月15日 14:00

　　地   点：岳阳路320号 上海生科院生理楼报告厅 　　

　　简   介：G Kelly, S Glaser, PN Kelly, S Grabow, A Delbridge, JM Adams, M Herold, and A Strasser

　　The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia

　　Impaired apoptosis is considered one of the prerequisites for the development of most, if not all, cancers, but the mechanisms that guarantee the sustained survival of most cancer cells remain unknown. Members of the Bcl-2 family are key regulators of apoptosis and include proteins essential for cell survival and those required to initiate cell death. Studies with transgenic mice have shown that over-expression of Bcl-2 or related pro-survival family proteins, such as Bcl-xL or Mcl-1, can promote tumorigenesis, particularly in conjunction with mutations that deregulate cell cycle control, such as deregulated c-myc expression. It is, however, not known whether expression of pro-survival Bcl-2 family members under endogenous control is required to maintain the survival of cells undergoing neoplastic transformation. Using E?-myc transgenic mice, a well-characterized model of human Burkitt‘s lymphoma, and mice, we investigated the role of endogenous Bcl-2 in lymphoma development. Bcl-2 was found to be dispensable for the development of E?-myc pre-B/B lymphoma. In contrast, loss of Bcl-xL and even more remarkable, loss of a single allele of Mcl-1 greatly impaired lymphoma development.

　　Experiments with inducible knockout mice demonstrated that Mcl-1 but not Bcl-xL is essential for the sustained survival and expansion of Myc-driven malignant pore-B/B lymphoma. Remarkably, even loss of one Mcl-1 allele greatly impaired lymphoma growth. These findings were translated into using lymphoid malignancies by using inducible expression of selective antagonists of distinct pro-survival Bcl-2 family members. Such studies showed that Mcl-1 is also critical for the sustained survival and expansion of Burkitt Lymphoma, a Myc-driven malignancy.

　　These observations indicate that (even relatively weak) targeting of Mcl-1 may be an attractive strategy for the treatment of Myc-driven hematological malignancies.