What doesn’t kill you makes you stronger – bcl-2 promotes survival independent of proliferation

TITLE Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells

AUTHORS Vaux DL, Cory S, Adams JM

JOURNAL Nature. 1988;335(6189):440-442. doi: 10.1038/335440a0. PMID: 3262202

Combination therapy with the BCL-2 inhibitor, venetoclax, and hypomethylating agents produces high response rates in elderly patients with acute myeloid leukemia unfit for induction chemotherapy, setting a new standard of care for these patients.¹ These clinical results build on decades of fundamental, translational, and clinical research into BCL-2 and apoptosis.

The bcl-2 gene (now known as BCL2) was originally discovered in 1984 by Yoshihide Tsujimoto in Croce’s laboratory; he identified it as the fusion partner with the immunoglobulin heavy chain locus in patients with B-cell malignancies and the t(14;18) translocation.² Subsequently, Reed et al. reported that bcl-2 was an oncogene, the first oncogene identified without a viral counterpart. However, the biological function and mechanism by which bcl-2 promoted malignancy remained unknown.

In a landmark paper published in 1988, Drs. Vaux, Cory and Adams described the first cellular mechanism of action of bcl-2.³ In their letter to Nature, a paper with three figures and neither supplementary material nor volumes of extended data, they showed that overexpression of bcl-2 prevented cell death. Interleukin (IL)-3-dependent FDCP1 myeloid cells were transduced with human bcl-2 cDNA and then IL-3 was withdrawn. All control and c-myc-transduced FDC-P1 cells died 4 days after IL-3 withdrawal. In contrast, 60% of the cells overexpressing bcl-2 remained viable. Although viable, cells overexpressing bcl-2 did not proliferate and did not become tumorigenic when injected into mice. The authors concluded that bcl-2 functions as an oncogene by promoting prolonged cell survival, independent of its effects on cell proliferation. Subsequently, bcl-2 was shown to protect cells from a specific mechanism of cell death, called apoptosis.

Over the following years and decades, a clearer picture of the mechanisms of action of bcl-2 emerged. A family of pro- and anti-apoptotic proteins structurally related to BCL-2 were identified. BCL-2 and its family members were localized to the mitochondrial outer membrane where they regulated mitochondrial membrane potential. Inhibiting BCL-2 led to a collapse of mitochondrial membrane potential and release of mitochondrial proteins, including cytochrome c, which triggered apoptosis. However, the book on bcl-2 is not yet closed. Even 30 years later, new functions for bcl-2 continued to be identified, including its ability to regulate T-cell immune function.

Figure 1.Overexpression of bcl-2 protects cells from cell death. Interleukin (IL)-3-dependent FDC-P1 myeloid cells were transduced with bcl-2 cDNA. After transduction, cells were washed to remove IL-3 from the culture media. Cell viability was measured by flow cytometry. Overexpression of bcl-2 protected cells from death after IL-3 withdrawal.

In 2001, the three-dimensional structure of BCL-2 was solved, paving the way for the identification of small molecules that bind BCL-2 and block its interaction with inhibitory pro-apoptotic proteins. Through iterative rounds of structure-guided medicinal chemistry, the selective BCL-2 inhibitor venetoclax was identified. Thirty-six years after the original identification of bcl-2 by Tsujimoto, a randomized clinical trial demonstrated the superiority of venetoclax in combination with azacitidine over azacitidine alone in elderly patients with newly diagnosed acute myeloid leukemia.¹

Until Vaux’s discovery, the prevailing opinion was that mutations in cancer-associated genes promoted malignancy by causing uncontrolled cellular proliferation. For the first time, Vaux et al. showed that oncogenes could act by blocking cell death. This discovery provided a new hallmark of cancer – the ability of cancer cells to resist cell death. It helped spark research into cell death mechanisms of cancer, and strategies to selectively target cell death pathways in cancer cells.

Footnotes

Correspondence

Aaron.Schimmer@uhn.ca

Disclosures

ADS has received research funding from Takeda Pharmaceuticals, BMS and Medivir AB, and consulting fees/honoraria from Takeda, Novartis, Jazz, BMS, Astra Zeneca, and Otsuka Pharmaceuticals. ADS is named on a patent application for the use of DNT cells to treat AML. ADS holds the Ronald N. Buick Chair in Oncology Research.