The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

Abstract

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main 'hallmarks of cancer', BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

Keywords: B-cell lymphoma 2; BH3-mimetics; chronic lymphocytic leukemia.

Figure 1.

Role of BCL2 and related proteins in the regulation of apoptosis. Signals of damage or derangement (violation of checkpoints, instability of the genome, activation of oncogenes) induce overexpression of pro-death BCL2 homology 3 (BH3)-only proteins. These proteins are functionally subdivided into activator (left) and sensitizer (right) protein families. Activator BH3-only proteins such as BID (BH3-interacting domain death agonist) and BIM (BCL2-like 11) induce effector multi-domain proapoptotic protein overexpression such as BAX (BCL2-associated X) and BAK (BCL2 antagonist/killer 1). This, in turn, leads to mitochondrial changes and apoptosis. Multi-domain anti-apoptotic proteins such as BCL2 oppose this process by sequestering activators, which limits contact with effectors, or by sequestering activated effectors. Sensitizer BH3-only proteins such as BAD (BCL2-associated agonist of cell death) act as selective inhibitors of anti-apoptotic proteins. Arrows and blunted arrows represent activation and inhibition, respectively. BAD, sensitizer BH3-only protein; BAK, BCL2 antagonist/killer 1; BAX, BCL2-associated X; BCL2, B-cell lymphoma 2; BCL-W, BCL2–like protein 2; BCL-XL, BCL extra-long; BFL-1, BCL2–related gene expression in fetal liver; BH3, BCL2 homology 3; BID, BH3-interacting domain death agonist; BIM, BCL2-like 11; BMF, BCL2 modifying factor; HRK, hara-kiri BCL2 interacting protein; MCL1, myeloid cell leukemia 1; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; PUMA, p53 upregulated modulator of apoptosis.

Figure 2.

Control of apoptosis by the BCL2 family of proteins. In normal mature B-cells (upper panel), BCL2 maintains cellular viability by blocking apoptosis. When a biological stress signal appears (middle panel), such as DNA or microtubular damage, cytokine deprivation or oxidative stress, the BH3 (BCL2 homology 3)-only proteins are activated. These proteins allow apoptosis to occur by binding to and inactivating BCL2 and related anti-apoptotic proteins. Some BH3-only proteins can directly activate BAX (BCL2-associated X) or BAK (BCL2 antagonist/killer 1) in malignant lymphoid cells (lower panel), stress-induced apoptosis may be impaired through a number of different mechanisms including overactivity of the anti-apoptotic BCL2 proteins (lower panel, upper row), reduced BH3-only protein expression via TP53 gene disruption (tumor protein 53, lower panel, middle row) and loss of BAX or BAK (lower panel, lower row). Black arrows and black blunted arrows represent activation or inhibition, respectively. Grey arrows and grey blunted arrows represent weakened activation or inhibition, respectively, due to biological influences acting upon them. BAK, BCL2 antagonist/killer 1; BAX, BCL2-associated X; BCL2, B-cell lymphoma 2; BH3, BCL2 homology 3; MCL1, myeloid cell leukemia 1; NOXA, phorbol-12-myristate-13-acetate-induced protein 1; PUMA, p53 upregulated modulator of apoptosis.

Figure 3.

Venetoclax original and modified administration schedule. The upper panel shows the venetoclax administration schedule in the original dose-escalation cohort. On day −7 (7 days before week 1), an initial single 50 mg dose was administered to 50 patients and a 20 mg dose to 3 patients. Daily administration of a 50 mg dose started in week 1 and was increased to 100–400 mg in week 2. By week 3, patients had reached the designated group dose (150–1200 mg per day). The lower panel shows the modified administration schedule for the 60 patients in the expansion cohort. Daily administration started with 20 mg per day, followed by weekly ramp-up in three steps to 400 mg. Pts, patients.