B-cell lymphoma 2 (Bcl-2) G101V mutant (Bcl-2 G101V)

The B-cell lymphoma 2 (Bcl-2) G101V mutant is a clinically significant variant of the Bcl-2 protein, which serves as a key anti-apoptotic regulator in the intrinsic mitochondrial pathway [10, 15]. This specific mutation involves a glycine-to-valine substitution at position 101, located within the BH3-binding groove of the protein [7, 13]. It was first identified as a major driver of acquired resistance in patients with chronic lymphocytic leukemia (CLL) who relapsed after initial successful treatment with the Bcl-2 inhibitor venetoclax [1, 17]. The G101V substitution creates a structural knock-on effect that displaces neighboring residues, such as E152, thereby reducing the binding affinity of venetoclax by approximately 180-fold [13, 14]. Despite this loss of drug binding, the mutant protein retains its biological function of sequestering pro-apoptotic proteins like BAX and BIM, allowing cancer cells to survive and proliferate [1, 13]. The emergence of this mutant has necessitated the development of next-generation Bcl-2 inhibitors, such as sonrotoclax (BGB-11417), which are designed to overcome the steric hindrance caused by the mutation and restore apoptotic signaling in resistant cells [3, 4]. Detection of the G101V mutation is now used as a biomarker to monitor for impending relapse in patients on venetoclax therapy [6, 18]. Understanding the structural basis of this mutation has provided a framework for the design of novel BH3-mimetics that can effectively target resistant hematologic malignancies [8, 12].

Other names

BCL2 G101V [1]BCL2 Gly101Val [17]B-cell lymphoma 2 Gly101Val mutation [7]

BH3-mimetic inhibition of anti-apoptotic proteins [8, 10]