Therapeutic targeting of Bcl-2 family for treatment of B-cell malignancies

Abstract

The BCL2 gene was discovered nearly 30 years ago, launching a field of scientific inquiry and medical research with the potential for delivering transformational therapeutics. Revealed by its involvement in chromosomal translocations of B-cell lymphomas, BCL2 is the founding member of a family of cell survival genes that endow cells with long life spans and provide protection from a myriad of cellular stresses, including chemotherapy. Anti-apoptotic Bcl-2 family members are commonly overexpressed in a variety of human malignancies through a diversity of genetic and epigenetic mechanisms. Here, we review therapeutic strategies for targeting Bcl-2 family members with an emphasis on B-cell malignancies, providing insights into their current promise and remaining challenges.

Keywords:

• apoptosis
• Bcl-2
• chemoresistance
• leukemia
• lymphoma

Financial & competing interests disclosure

J Huang and W Fairbrother are employees of Genentech, Inc., a member of the Roche Group, and J Reed is an employee of Roche. Editorial assistance was utilized in the production of this manuscript, and was provided by TB Gibson, of Evidence Scientific Solutions and funded by Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Bcl-2 and related anti-apoptotic proteins inhibit programmed cell death (apoptosis), thus promoting cell accumulation and contributing to chemoresistance.

• BCL2 becomes pathologically overexpressed in various malignancies, including B-cell lymphomas and leukemias that harbor chromosomal translocations activating the BCL2 gene, BCL2 gene amplification and loss of BCL2–suppressing microRNA-encoding genes.

• Strategies for neutralizing Bcl-2 and inducing apoptosis of leukemia and lymphoma cells have included short synthetic single-strand DNA (oligonucleotide) drugs that hybridize with BCL2 mRNA and small molecule chemicals that bind to Bcl-2 protein.

• Promising clinical results have been obtained using Bcl-2–selective small-molecule compounds to treat patients with relapsed/refractory chronic lymphocytic leukemia and non-Hodgkin lymphoma.

• Mechanisms of resistance to Bcl-2–selective therapeutics may include overexpression of other anti-apoptotic members of the Bcl-2 family, such as Mcl-1, Bcl-XL or Bfl-1.

Notes