SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.

 

Comments:

The information you provided describes a significant finding in the field of acute myeloid leukemia (AML) research. It states that the survival and growth of many AML samples and cell lines, regardless of their genetic characteristics such as RAS and p53 mutations, depend on a protein called SIRT5. SIRT5 is a lysine deacylase known to regulate multiple metabolic pathways.

The dependence on SIRT5 was observed specifically in AML cells and not in normal CD34+ cells. The study employed both SIRT5 knockdown and inhibition using a selective SIRT5 inhibitor called NRD167, and the results were comparable. Disrupting SIRT5 function through knockdown or inhibition induced apoptosis (programmed cell death) in AML cells.

The researchers also found that inhibiting SIRT5 led to reductions in oxidative phosphorylation and glutamine utilization, two important metabolic processes. Additionally, there was an increase in mitochondrial superoxide, a type of reactive oxygen species, which was mitigated by the introduction of superoxide dismutase 2, an enzyme that neutralizes superoxide.

Overall, these findings suggest that SIRT5 plays a crucial role in controlling and coordinating key metabolic pathways in AML. It implies that targeting SIRT5 could be a potential therapeutic strategy in AML treatment, as inhibiting its function resulted in cell death. This discovery identifies SIRT5 as a vulnerability in AML and opens up avenues for further research and the development of novel therapeutic approaches.

Related Products

Cat.No.	Product Name	Information
S9903	NRD167	NRD167 is a potent and selective SIRT5 inhibitor.

Related Targets

Sirtuin