Targeting the B-cell lymphoma/leukemia 2 family in cancer

Abstract

The B-cell lymphoma/leukemia 2 (BCL-2) family of proteins has attracted the attention of cancer biologists since the cloning of BCL-2 more than 25 years ago. In the intervening decades, the way the BCL-2 family controls commitment to programmed cell death has been greatly elucidated. Several drugs directed at inhibiting BCL-2 and related antiapoptotic proteins have been tested clinically, with some showing considerable promise, particularly in lymphoid malignancies. A better understanding of the BCL-2 family has also provided insight into how conventional chemotherapy selectively kills cancer cells and why some cancers are more chemosensitive than others. Further exploitation of our understanding of the BCL-2 family promises to offer improved predictive biomarkers for oncologists and improved therapies for patients with cancer.

Fig 1.

Three families of B-cell lymphoma/leukemia 2 (BCL-2) proteins govern the decision to undergo mitochondrial apoptosis. DNA damage, checkpoint violations, or oncogene activation generates pro-death BCL-2 homology 3 (BH3) –only proteins, which can be subdivided into activator and sensitizer subfamilies based on function. Activator BH3-only proteins such as BID and BIM activate effector multidomain proapoptotic proteins such as BAX and BAK, leading to mitochondrial permeabilization and commitment to apoptotic death. Multidomain antiapoptotic proteins such as BCL-2 oppose this process by sequestering activators and thereby limiting contact with effectors or by sequestering activated effectors. Sensitizer BH3-only proteins such as BAD act as selective inhibitors of antiapoptotic proteins. BCL-w, BCL-2–like protein 2; BCL-XL, BCL extra long; BFL-1, BCL-2–related gene expression in fetal liver; MCL-1, MCL-1, myeloid cell leukemia 1. Data adapted.

Fig 2.

Model of ABT-737–induced death at the mitochondria. Mitochondrial B-cell lymphoma/leukemia 2 (BCL-2) in chronic lymphocytic leukemia cells is typically occupied by BIM. ABT-737 displaces BIM, and BCL-2 becomes occupied by ABT-737. Freed BIM then interacts with BAX or BAK, leading to oligomerization, cytochrome c release and subsequent irreversible commitment to programmed cell death. When BCL-2 is occupied by activator BCL-2 homology 3 (BH3) –only proteins, the cancer cell is sensitive to treatment with ABT-737 and other chemotherapeutic agents. Data adapted.

Fig 3.

Priming is the proximity of a malignant cell to the threshold of apoptosis. (A) An unprimed cell is exposed to chemotherapy and pushed toward the threshold of apoptosis, but because it starts far from the threshold, this change is not enough to kill the cell. (B) A primed cell exposed to the same chemotherapy agent at the same dose is pushed the same distance toward the threshold of apoptosis, but because it starts closer to this threshold, the change is enough to push the cell over the edge, resulting in apoptotic cell death.

Fig 4.

BCL-2 homology 3 (BH3) profiling. (A) Single-cell suspensions derived from peripheral blood, bone marrow, lymph nodes, solid tumors, or normal tissue are permeabilized via digitonin and stained with JC-1. Permeabilized cells are then exposed to BH3-only peptides in a 384-well format, and the decay of ΔΨ_m is measured as fluorescence at 590 nm, via the JC dye, by plate reader. Note that for heterogeneous clinical samples, this process can be performed with fluorescence activated cell sorting and a BH3 profile derived for a cellular subpopulation of interest. Data adapted. (B) Comparison of mitochondrial priming among a variety of primary human cancers and normal tissues. Cancers with clinical follow-up were classified as known chemosensitive or known chemoresistant. Cancers classified as typically chemoresistant or typically chemosensitive lacked individual clinical follow-up data. Data shown are mean ± standard deviation across all specimens tested. Analysis of variance was used to demonstrate statistical significance between the different categories, with a Tukey's multiple comparison post-test. NS, not significant (ie, P > .05). (*) P < .01. (†) P < .001. Data adapted.