Bcl 2 on the brink of breakthroughs in cancer treatment
Bcl 2 is the founding member of a large family of proteins that regulate cell survival and cell death. Since its discovery in B cell lymphomas over 30 years ago, research on the biological functions and mechanisms of action of Bcl 2 family proteins in controlling cell life and death decisions has revealed important roles in multiple diseases, paving the way for at least one novel therapeutic agent. In this issue of Cell Death and Differentiation, several of the world's leaders in research on Bcl 2 family proteins provide complementary reviews covering multiple facets of this intriguing class of proteins, ranging from cellular and molecular mechanistic insights about how these proteins work and addressing their roles in evolution of programmed cell death mechanisms, mammalian development, cancer genetics, cancer biology and applications towards novel cancer therapies. With the recent approval by FDA of the orally bioavailable and highly selective Bcl 2 inhibitor, venetoclax, for some subtypes of chronic lymphocytic leukemia (CLL) Bcl 2 family proteins are now validated as promising drug targets, with the potential to provide significant advances in the standard of care for patients suffering from oncological maladies and possibly for certain non oncological diseases as well. The story of Bcl 2 began with discovery of the gene's involvement in chromosomal translocations found in nonHodgkin's lymphomas (NHLs) by the Croce group. Most lowgradeNHLs contain a t(14;18) chromosomal translocation that places the BCL 2 gene on chromosome 18 into juxtaposition with the immunoglobulin heavy chain locus on chromosome 14, thus driving high levels of BCL 2 gene expression in B cells. These NHLs are termed 'low grade' because the B cells accumulate without having a high proliferative rate, which was an early clue that BCL 2 operated in a manner distinct from previously discovered oncogenes (MYC, RAS, etc. by prolonging cell lifespan rather than by driving cell division. Croce and co workers review the journey that led to their discovery ofBCL 2. They also explain how they uncovered the mystery of why CLL B cells express very high levels of Bcl 2 mRNA and protein without genetic changes in the BCL 2 gene structure or sequence. For CLL, they homed in on 13q14 chromosomal deletions found in the majority of CLLs, leading them to discover the first example of genetic loss of microRNAencoding genes that serve as tumor suppressors. Croce and co workers describe how deletion and mutation of the gene cluster encodingmiR15 andmiR16 relieves Bcl 2 mRNA from silencing and explains at least in part the high levels of Bcl 2 expression seen inmost CLLs. Interestingly, the Croce group's investigations knocking out homologs of miR15/16 in mice suggest that these microRNAs oppose neoplasia by doing more than suppressing Bcl 2 expression, presumably via effects on additional target genes. Moreover, they discovered a homologous additional microRNA gene cluster (mir15b/ mir16.2) that when knocked out in mice also causes accumulation of CD5+ B lymphocytes, but has little effect on Bcl 2 expression, implicating other target genes. Adams and Cory review the seminal work from their laboratories that firmly established the antiapoptotic function of the Bcl 2 protein, thus revealing the world's first example of an anti apoptotic oncogene. They emphasize how enforced Bcl 2 expression overcomes the proapoptotic influence of oncogenic stress, caused by dysregulation of oncogenes such as C MYC and CYCLIN D1 (aka, BCL 1) that drive cellular proliferation. Consequently, malignant cells are often dependent on (addicted to) Bcl 2 or other antiapoptotic proteins to protect them from the apoptotic drive of oncogenic stress, thus illustrating why malignant cells should be selectively vulnerable to agents that inhibit Bcl 2 and thereby conferring a reasonable therapeutic index. They cite a recent example of Bcl 2 addiction in the case of acute myelogenous leukemias that harbor IDH1 (isocitrate dehydrogenase 1) gene mutations. The anti apoptotic role of Bcl 2 has also been linked to chemoresistance, making it more difficult to kill malignant cells with cytotoxic anticancer drugs. Montero and Letai review their work on dynamic BH3 (Bcl 2 homology 3) profiling as a means of ascertaining how 'primed' cancer cells are to undergo apoptosis, which correlates with clinical chemoresistance. The concept is that endogenous antagonists of the antiapoptotic Bcl 2 family proteins (such as Bad, Bim, Bid, Puma, Noxa, Bcl G, etc. bind via an amphipathic a helical domain called BH3 and thus synthetic BH3 peptides titrated into cancer cells can reveal how close or how far cells are from being driven into apoptosis. Dynamic BH3 profiling has shown correlations with clinical responses (tumor shrinkage) for leukemias and some types of solid tumors but the predictivity of this method for longer term patient outcomes (disease free or overall survival) merits further investigation. Also, because in vitro analysis of isolated leukemia and cancer cells fails to recapitulate the complexity of the in vivo tumor
Cell Death and Differentiation