10 January 2022

Vulnerability found in metabolism of lymphoma cells

 

Scientists have identified a metabolic feature that could be used to halt the growth of diffuse large B cell lymphoma (DLBCL) cells.

The metabolism of these cells is regulated by a protein called SIRT3 which works with another protein, ATF4.

A team from Weill Cornell Medicine in New York, USA, found that silencing ATF4 in DLBCL cells can deprive them of nutrients such as amino acids, fooling the cells into starving themselves. Furthermore, reducing the production of SIRT3 can also increase lymphoma cell death.

In the journal Blood Cancer Discovery, the researchers write: “We identify a SIRT3-ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimise amino acid uptake and utilisation.”

The team found that a drug which inhibits the activation of ATF4 increases the effectiveness of a SIRT3-blocking drug – killing more DLBCL cells than either drug on its own.

They add that this SIRT3-ATF4 link is crucial for DLBCL, regardless of subtype, “which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.”

Co-senior author Dr Ari Melnick said: “ATF4 represents a crucial and exploitable vulnerability in diffuse large B cell lymphomas - and one that they appear to share regardless of the specific genetic mutations that trigger them.”

Researcher Dr Hening Lin added: “One of the really interesting things about this study is that it shows how nutrient conditions, in principle even from patients’ diets, can profoundly affect cancer-cell activity.

“We are excited to consider the translational potential of this finding in treating lymphoma.”

Source:

Li M, Teater MR, Hong JY, Park NR, Duy C, Shen H, Wang L, Chen Z, Cerchietti L, Davidson SM, Lin H, and Melnick AM. (2021) “Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.” Blood Cancer Discovery, doi: 10.1158/2643-3230.BCD-20-0183

Link: https://bloodcancerdiscov.aacrjournals.org/content/early/2021/12/11/2643-3230.BCD-20-0183

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