New research suggests T-cell acute lymphoblastic leukemia (T-ALL) cells use the tricarboxylic acid (TCA) cycle to support their growth and survival.
Investigators say the findings could aid the development of therapeutics that can kill T-ALL cells by targeting an enzyme that exists in the TCA cycle—dihydrolipoamide S-succinyltransferase (DLST).
The team described this research in the journal Leukemia.
“Researchers have wrongly assumed that cancer cells do not use the TCA cycle to support their growth,” said study author Hui Feng, MD, PhD, of Boston University Medical Center in Massachusetts.
“Our new findings provide solid evidence that these cancer cells depend on the TCA cycle for their survival. Additionally, we demonstrated the importance of DLST in T-cell leukemia development and have identified a targetable enzyme for T-cell leukemia treatment.”
For this study, the investigators set out to examine the mechanisms underlying MYC-mediated tumorigenesis in T-ALL.
They used a zebrafish model of MYC-induced T-ALL to screen for genes that contribute to disease onset. The results suggested the TCA-cycle enzyme DLST is an important contributor to T-ALL development.
And experiments showed that heterozygous inactivation of DLST significantly delayed disease onset in the zebrafish, apparently without affecting the development of the fish.
Further analysis revealed that inhibiting the activity of DLST could effectively kill human T-ALL cells. Specifically, RNAi knockdown of DLST decreased cell viability and induced apoptosis in human T-ALL cell
lines.
The investigators found that knockdown of DLST disrupted the TCA cycle in the human T-ALL cells. But adding succinate, the downstream TCA-cycle intermediate, to the cells rescued defects in cell viability caused by DLST knockdown.
The investigators said the therapeutic benefit of DLST inhibition may extend to cancers other than T-ALL as well.
