Abstract

Impaired apoptosis is considered a prerequisite for the development of most, if not all, cancers, but the mechanisms that guarantee sustained survival of most cancer cells remain unknown. Members of the BCL-2 family of proteins 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 survival of cells undergoing neoplastic transformation. Using Eµ-Myc transgenic mice, a well-characterized model of human Burkitt’s lymphoma, and other murine cancer models, we investigated the role of BCL-2 pro-survival proteins when expressed under endogenous control in lymphoma development. BCL-2 was found to be dispensable for development of Eµ-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-2 or BCL-XL is essential for sustained survival and expansion of c-MYC-driven malignant pre-B/B lymphoma, AML driven by various oncogenes and T cell lymphoma driven by loss of p53. Remarkably, even loss of one allele of Mcl-1 greatly impaired lymphoma growth. These findings were translated into human lymphoid malignancies by using inducible expression of guide RNAs that target different Bcl-2 family members. Such studies showed that MCL-1 is critical for sustained survival and expansion of Burkitt Lymphoma, a c-MYC-driven malignancy. These observations indicate even relatively weak targeting of MCL-1 may be an attractive strategy for treatment of c-MYC-driven hematological malignancies and possibly other cancers driven by different oncogenic lesions.