Work

The UBE2J2/UBE2K-MARCH5 ubiquitination machinery regulates apoptosis in response to venetoclax in acute myeloid leukemia

Year: 2024

Type: article

Abstract: Evasion of apoptosis is crucial for the growth, survival and chemoresistance of many cancer types, including acute myeloid leukemia (AML); thus, the reactivation of apoptosis can be exploited as a therapeutic approach. Apoptosis induction is mainly controlled by the balance between anti-apoptotic and pro-apoptotic BCL2 family proteins, which determines the oligomerization of effectors BAX and BAK and thus the permeabilization of mitochondrial membranes [ 1 ]. Venetoclax, a selective inhibitor antagonizing the anti-apoptotic protein BCL2, has emerged as a promising therapy in AML. Despite high response rates in combination with hypomethylating agents, some patients display upfront resistance, and most patients will ultimately relapse [ 2 , 3 , 4 ]. Therefore, identification of synergistic targets for combination therapies with venetoclax is important for improving the clinical application of this drug. Several potential targets have been revealed. For instance, inhibiting BCLXL or MCL1, two anti-apoptotic BCL2 family members, can trigger synergistic anti-tumor activity with venetoclax [ 2 ]. We also reported that inhibition of the RING-type ubiquitin E3 ligase MARCH5 can induce BAX/BAK-dependent apoptosis and lead to venetoclax sensitization in AML cells [ 5 ].

Source: Leukemia

DOI: 10.1038/s41375-024-02178-x

Authors: Shan Lin, Constanze Schneider, Angela H. Su, Gabriela Alexe, David E. Root, Kimberly Stegmaier

Institutions: Broad Institute, Dana-Farber Cancer Institute, Boston Children's Hospital, Dana-Farber/Harvard Cancer Center

Language: English

Topic: Cell death mechanisms and regulation

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,990