(B-cell lymphoma 2
), encoded in humans by the BCL2 gene
, is the founding member of the Bcl-2 family
of regulator proteins
that regulate cell death (apoptosis
), by either inducing (pro-apoptotic) or inhibiting (anti-apoptotic) apoptosis.
Bcl-2 is specifically considered an important anti-apoptotic protein but it is NOT considered a proto-oncogene because it is not a growth signal transducer.
The two isoforms
of Bcl-2, Isoform 1, also known as 1G5M, and Isoform 2, also known as 1G5O/1GJH, exhibit a similar fold. However, results in the ability of these isoforms to bind to the BAD
proteins, as well as in the structural topology and electrostatic potential
of the binding groove, suggest differences in antiapoptotic activity for the two isoforms 
BCL-2 is localized to the outer membrane of mitochondria, where it plays an important role in promoting cellular survival and inhibiting the actions of pro-apoptotic proteins. The pro-apoptotic proteins in the BCL-2 family, including Bax
, normally act on the mitochondrial membrane to promote permeabilization and release of cytochrome C
, that are important signals in the apoptosis cascade. These pro-apoptotic proteins are in turn activated by BH3-only proteins, and are inhibited by the function of BCL-2 and its relative BCL-Xl
There are additional non-canonical roles of BCL-2 that are being explored. BLC-2 is known to regulate mitochondrial dynamics, and is involved in the regulation of mitochondrial fusion and fission. Additionally, in pancreatic beta-cells, BCL-2 and BCL-Xl
are known to be involved in controlling metabolic activity and insulin secretion, with inhibition of BCL-2/Xl showing increasing metabolic activity, but also additional ROS production; this suggests it has a protective metabolic effect in conditions of high demand.
Cancer can be seen as a disturbance in the homeostatic
balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in lymphomas
. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone does not cause cancer. But simultaneous over-expression of Bcl-2 and the proto-oncogene myc
may produce aggressive B-cell
malignancies including lymphoma.
In follicular lymphoma
, a chromosomal translocation
commonly occurs between the fourteenth and the eighteenth chromosomes
— t(14;18) — which places the Bcl-2 gene from chromosome 18 next to the immunoglobulin
heavy chain locus on chromosome 14. This fusion gene is deregulated, leading to the transcription of excessively high levels of Bcl-2.
This decreases the propensity of these cells for apoptosis.
Apoptosis plays an active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens
via both central and peripheral tolerance. In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.
The autoimmune disease type 1 diabetes
can be caused by defective apoptosis, which leads to aberrant T cell AICD
and defective peripheral tolerance. Due to the fact that dendritic cells
are the immune system’s most important antigen-presenting cells
, their activity must be tightly regulated by mechanisms such as apoptosis. Researchers have found that mice containing dendritic cells that are Bim
-/-, thus unable to induce effective apoptosis, suffer autoimmune diseases
more so than those that have normal dendritic cells.
Other studies have shown that dendritic cell lifespan may be partly controlled by a timer dependent on anti-apoptotic Bcl-2.
Apoptosis plays an important role in regulating a variety of diseases. For example, schizophrenia is a neurodegenerative disease
that may result from an abnormal ratio of pro- and anti-apoptotic factors.
Some evidence suggests that this may result from abnormal expression of Bcl-2 and increased expression of caspase-3
Antibodies to Bcl-2 can be used with immunohistochemistry
to identify cells containing the antigen. In healthy tissue, these antibodies react with B-cells in the mantle zone
, as well as some T-cells
. However, positive cells increase considerably in follicular lymphoma
, as well as many other forms of cancer. In some cases, the presence or absence of Bcl-2 staining in biopsies
may be significant for the patient’s prognosis
or likelihood of relapse
Targeted and selective Bcl-2 inhibitors currently in the clinic include :
An antisense oligonucleotide
(G3139) was developed by Genta Incorporated
to target Bcl-2. An antisense
DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug
is a short sequence of RNA that hybridises with and inactivates mRNA, preventing the protein
from being formed.
Human lymphoma cell
proliferation (with t(14;18) translocation) could be inhibited by antisense RNA
targeted at the start codon
region of Bcl-2 mRNA
. In vitro
studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA.
These showed successful results in Phase I/II trials for lymphoma. A large Phase III trial was launched in 2004.
As of 2016, the drug had not been approved and its developer was out of business.
In the mid-2000s, Abbott Laboratories
developed a novel inhibitor of Bcl-2, Bcl-xL and Bcl-w, known as ABT-737. This compound is part of a group of BH3 mimetic small molecule inhibitors (SMI) that target these Bcl-2 family proteins, but not A1 or Mcl-1. ABT-737 is superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro
studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.
ABT-737 does not directly induce apoptosis; it enhances the effects of apoptotic signals and causes single-agent-mechanism-based killing of cells in small-cell lung carcinoma and lymphoma lines.
In animal models, it improves survival, causes tumor regression and cures a high percentage of mice.
In preclinical studies utilizing patient xenografts
, ABT-737 showed efficacy for treating lymphoma and other blood cancers.
Because of its unfavorable pharmacologic properties ABT-737 is not appropriate for clinical trials, while its orally bioavailable
derivative navitoclax (ABT-263)
has similar activity on small cell lung cancer
(SCLC) cell lines and has entered clinical trials.
While clinical responses with navitoclax were promising, mechanistic dose-limiting thrombocytopoenia
was observed in patients under treatment due to Bcl-xL inhibition in platelets
Due to dose-limiting thrombocytopoenia of navitoclax as a result of Bcl-xL inhibition, Abbott Laboratories
successfully developed the highly selective inhibitor venetoclax
(ABT-199), which inhibits Bcl-2, but not Bcl-xL or Bcl-w.
Clinical trials studied the effects of venetoclax, a BH3-mimetic drug designed to block the function of the Bcl-2 protein, on patients with chronic lymphocytic leukemia
Good responses have been reported and thrombocytopoenia was no longer observed.
A phase 3 trial started in Dec 2015.
It was approved by the US FDA
in April 2016 for CLL associated with 17-p deletion.
This is the first FDA approval of a protein-protein inhibitor of BCL-2.