B-cell lymphoma 2 D103Y mutant (Bcl-2 D103Y)

Bcl-2 D103Y is a mutant form of the B-cell lymphoma 2 (Bcl-2) protein, which serves as a critical regulator of the intrinsic apoptotic pathway by preventing the release of cytochrome c from mitochondria [6, 10]. The D103Y mutation involves a substitution of aspartate with tyrosine at position 103, located within the BH3-binding groove (specifically the P4 pocket) of the protein [1, 2]. This mutation is primarily recognized as an acquired resistance mechanism in patients with chronic lymphocytic leukemia (CLL) who have undergone prolonged treatment with the Bcl-2 inhibitor venetoclax [1, 12]. Structurally, the D103Y substitution disrupts a key hydrogen bond with venetoclax, significantly reducing the drug's binding affinity while maintaining the protein's physiological ability to sequester pro-apoptotic partners like BIM [1, 3]. Consequently, cancer cells harboring this mutation can evade venetoclax-induced apoptosis, leading to clinical relapse [2, 14]. Research is currently focused on developing next-generation Bcl-2 inhibitors, such as sonrotoclax and lisaftoclax, which may overcome the resistance conferred by D103Y and other co-occurring mutations like G101V [8, 11].

Other names

BCL2 D103YB-cell lymphoma 2 Asp103TyrBcl-2 D103Y mutationAsp103Tyr mutant of Bcl-2

Inhibition of anti-apoptotic Bcl-2 protein to induce apoptosis