Posted: Friday, April 23, 2021
A group of researchers discovered that a majority of acute myeloid leukemia (AML) cells appear dependent on the enzyme sirtuin 5 (SIRT5), and inhibition of this enzyme may be detrimental to the survival of AML cells. A deacylase with desuccinylase, demalonylase, and deglutarylase activity, SIRT5 is implicated in a number of metabolic processes. Dongqing Yan, PhD, of the University of Utah, Salt Lake City, presented these data on behalf of her colleagues at the American Association for Cancer Research (AACR) Virtual Annual Meeting 2021 (Abstract LB109).
The team performed a short hairpin RNA screen targeting 1,287 genes on 12 different AML samples to identify SIRT5 as a top candidate. They demonstrated that knockdown of SIRT5 in AML cells may lead to inhibition of cell growth and colony formation while increasing apoptosis in 15 SIRT5-dependent cell lines. An additional seven cell lines were noted to be independent of SIRT5, however, SIRT5 dependence did not correlate with basal SIRT5 expression or AML-related mutations. Knockdown of SIRT5 in primary AML samples demonstrated a reduction in colony formation, with no effect on cord blood samples.
Xenograft modeling with SIRT5-dependnet AML cell lines showed that knockdown of SIRT5 led to indefinitely prolonged survival with no signs of leukemia. Bone marrow transplant with SIRT5-null cells likewise showed reduced leukemia cell burden and splenomegaly, with an apparent survival benefit. SIRT5 knockdown was found to exert its effect via profoundly reducing oxidative phosphorylation and glycolysis while increasing mitochondrial superoxide in SIRT5-dependent cells.
Researchers then used NRD167, a novel SIRT5 inhibitor, to target SIRT5 in AML cells. As expected, NRD167 reduced cell proliferation, induced apoptosis, and reduced oxidative phosphorylation in SIRT5-dependent cells. Additionally, NRD167 inhibited colony formation in AML patient samples, but not in cord blood samples, suggesting that SIRT5 expression is not needed for healthy hematopoietic cells. A xenograft model using AML-patient derived cells showed that ex vivo administration of NRD167 trended toward prolonged survival.
Disclosure: For Dr. Deininger’s disclosures, visit abstractsonline.com. All other authors reported no conflicts of interest.