Deregulation of BCL2 family proteins in B-cell lymphomas — molecular, pathogenetic, clinical and therapeutic implications

Abstract

Ability of differentiating B-cells to respond to death signals is essential for the maintenance of
immune system homeostasis. Abnormalities in the execution of these signals are therefore
dangerous and potentially oncogenic. BCL2 (B-cell CLL/lymphoma 2) family proteins act as
a critical regulators of apoptosis. The BCL2 family consist of pro-survival and pro-apoptotic
proteins, playing distinct roles in the transduction of death signals. Deregulated expression of
these proteins is a frequent feature of B-cell tumors and might occur through structural and functional mechanisms. Aberrant expression of these proteins is an important lesion for initiation
of B-cell tumors but also facilitating survival of tumor cells. Clinically, abnormal expression of
BCL2 family members contribute to chemoresistance of tumor cells and is associated with
inferior survival. Given the role of BCL2 protein family and their clinical implications for B-
-cell tumor biology, pharmacological targeting in BCL2 family is a particularly rational strategy.
Therapeutic agents developed to restore the BCL2 family-dependent life-death decisions are
now entering clinical trials. These new drugs can either decrease the abundance of BCL2
family proteins by antisense-mediated mechanisms or modulate the interactions between
proteins, such as small molecule BH3 mimetics and stapled peptides. Herein, we review the
molecular mechanism of BCL2 family deregulation, its consequences for the biology and
clinical behavior of B-cell tumors and discuss the results of available clinical trials.