BCL-2 in Cancer

Tumor cells may become dependent on BCL-2 for survival

Similar to oncogene addiction, in which tumor cells rely on a single dominant gene for survival, tumor cells may also become dependent on BCL-2 in order to survive.6 In response to stress signals, malignant cells may express pro-apoptotic activators. Some cancer cells overexpress BCL-2,1 which can dampen this pro-apoptotic response. The result is in many cases an abundance of pro-apoptotic activators bound and sequestered by BCL-2. In this scenario, cancer cells are thought to be “primed” for apoptosis, in that they may contain sufficient amounts of the pro-apoptotic activators, if displaced from BCL-2, to induce programmed cell death (Figure 3.1). Cancers that depend on BCL-2 for survival in this way are likely to be sensitive to BCL-2 modulation.10

Figure 3.1 Cell priming

Mitochondrion of primed cancer tumor cell and BCL-2 binds pro-apoptotic proteins to cancer cells primed for programmed cell death image

Expression in disease

The dynamic role of pro- and anti-apoptotic proteins, among other proteins, may alter the significance of increased BCL-2 expression in human disease. However, the wide variety of cancer types associated with aberrant expression of BCL-2 is consistent with its role as an apoptotic regulator (Table 3.2).

BCL-2 expression in leukemia

Less than 5% of patients with chronic lymphocytic leukemia harbor a detectable BCL-2 gene rearrangement, although the vast majority overexpress BCL-2.11 Increased expression of BCL-2 is also found frequently in acute myeloid leukemia8 and in nearly all patients with acute lymphocytic leukemia.13

BCL-2 expression in non-Hodgkin lymphoma

In follicular lymphoma, an estimated 90% of patients harbor a t(14;18) chromosomal translocation in tumor cells,14 which is thought to cause overexpression of BCL-2 protein.15 More than 40% of diffuse large B-cell lymphoma patients were categorized as having relatively high BCL-2 expression.16

BCL-2 expression in solid tumors

BCL-2 may also play a role in nonhematologic tumors, and inappropriate expression has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers.17-20 In small cell lung cancer, high BCL-2 expression in >90% of patients has been reported.19 Ovarian, neuroblastoma, bladder, colorectal, and some head and neck cancers have all exhibited significant levels of BCL-2 expression.21-25

Table 3.2 Select clinical evidence in cancer

Malignancy

Findings in human errors

Chronic lymphocytic leukemia (CLL) Relatively high level of BCL-2 expression documented in 95% of CLL cases compared to normal peripheral blood lymphocytes11
Acute myeloid leukemia (AML) High expression of BCL-2 associated with poor response to chemotherapy12
Acute lymphocytic leukemia (ALL) High levels of BCL-2 are found in nearly all patients with ALL13
Follicular lymphoma (FL) BCL-2 is overexpressed as a result of a chromosomal translocation in approximately 90% of follicular center B-cell lymphomas14
Diffuse large B-cell lymphoma (DLBCL) Chromosomal translocations affecting BCL-2 occur in approximately 20% of DLBCL26 BCL-2 expression correlates negatively with overall survival within a specific subgroup of DLBCL27
Diverse solid tumors Inappropriate expression of BCL-2 has been observed in solid tumors such as prostate, breast, and small cell and non-small cell lung cancers17-20