Aggressive and relatively common lymphomas called diffuse large B cell lymphomas (DLBCLs) have a critical metabolic vulnerability that can be exploited to trick these cancers into starving themselves, according to a new study.

The researchers, whose study was published Dec. 13 in Blood Cancer Discovery, showed that a protein called ATF4, a genetic master-switch that controls the activities of hundreds of genes, has a key role in supporting the fast growth of DLBCLs. The scientists found that silencing ATF4 in DLBCL cells essentially fools the cells into starving themselves and slowing their growth — and that targeting ATF4 along with a closely related metabolic protein, SIRT3, even further enhances this cancer-killing effect.

«ATF4 represents a crucial and exploitable vulnerability in DLBCLs — and one that they appear to share regardless of the specific genetic mutations that trigger them,» said study co-senior author Dr. Ari Melnick, the Gebroe Family Professor of Hematology / Oncology in the Division of Hematology and Clinical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Dr. Hening Lin, a professor in the Department of Chemistry and Chemical Biology at Cornell University in Ithaca and a Howard Hughes Medical Institute investigator, is the other co-senior author of the study.

Lymphomas are blood cancers that usually originate from immune cells such as B cells, the producers of antibodies. The vast majority of lymphomas are so-called non-Hodgkin lymphomas, and DLBCLs account for about a third of these, or roughly 25,000 cases per year in the United States. DLBCLs are relatively fast-growing and aggressive, and despite many advances in lymphoma treatment in recent decades, about 40 percent of cases are not cured — a statistic that underscores the need for new treatment strategies.

Dr. Melnick, Dr. Lin and their colleagues set out in the study to investigate SIRT3, which resides in mitochondria, the tiny, oxygen-burning fuel reactors in our cells that are essential for powering cellular activities. The research team had discovered in a 2019 study that SIRT3 strongly supports the growth and survival of DLBCLs by speeding up the biochemical reactions that produce the molecular building blocks cells need to proliferate.

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