Does SIRT1 Play a Role in Chronic Myeloid Leukemia Development?
Posted: Wednesday, July 31, 2019
A team of researchers led by senior author Ravi Bhatia, MD, of the University of Alabama at Birmingham, showed that the protein sirtuin 1 (SIRT1) may play an important role in the development of chronic myeloid leukemia (CML). The paper, published in The Journal of Clinical Investigation, shows that SIRT1 and its downstream effects may alter mitochondrial respiration in leukemia stem cells to promote leukemia development.
“Our research reveals new knowledge and concepts regarding the role of SIRT1 in metabolic regulation of hematopoietic stem cell and leukemic stem cell maintenance, growth, and resistance,” Dr. Bhatia said in an institutional press release. “This raises the possibility of developing improved strategies to target kinase-independent metabolic alterations.”
The team relied on animal studies, flow cytometry, and RNA sequencing to establish a role for SIRT1. SIRT1 normally works to activate a transcriptional coactivator, PGC-1–alpha, to enhance mitochondrial DNA replication and gene expression. The team found that SIRT1 deletion has minimal effect on hematopoiesis, but it impairs leukemia development in transgenic CML mice. The deletion of SIRT1 inhibited the expression of mitochondrial genes in CML stem and progenitor cells and reduced mitochondrial respiration.
These mitochondrial alterations are kinase dependent, and the addition of tyrosine kinase inhibitors may enhance the inhibition of CML hematopoiesis in mice with SIRT1 deletions. PGC-1–alpha contributes to oxidative phosphorylation as well as resistance to tyrosine kinase inhibitors. PCG-1–alpha inhibitors reduced mitochondrial oxygen consumption and may act similarly to SRT1 deletion.
Disclosure: The study authors reported no conflicts of interest.