SIRT1 Plays Key Role in Preventing Leukemia Stem Cell Elimination

The stress-response protein SIRT1 plays an important role in the regenerating potential of chronic myeloid leukemia (CML) and whether primitive leukemia stem cells resist elimination during remission, according to a new study published in The Journal of Clinical Investigation.

Patients with CML can be treated with tyrosine kinase inhibitors, which are effective and can lead to deep remission and prolonged survival. However, primitive leukemia stem cells remain a major barrier to a cure, meaning that most patients will need to use inhibitor treatment indefinitely. During this long-term treatment, patients face risks of drug noncompliance, financial burden, and toxicity. The new study showed that the SIRT1 protein helps to enhance oxidative phosphorylation by the mitochondria in leukemia stem cells.

"Our studies provide a conceptual advance and new biological insights regarding the activity of SIRT1 and its role in CML leukemic stem cells," senior author and professor of medicine Ravi Bhatia, MD, director of the Division of Hematology and Oncology, and interim director of the O'Neal Comprehensive Cancer Center at The University of Alabama Birmingham, said in a statement.

Research was conducted in healthy mice and mice with CML. Each group of mice had a subgroup with SIRT1 deletion. Investigators found that SIRT1 deletion had minimal effect on hematopoiesis in healthy mice. However, in the CML mice group, SIRT1 deletion impaired leukemia development. Mice with CML without the SIRT1 deletion developed progressive neutrophilic leukocytosis and increased morbidity from leukemia, according to the study.

Investigators also observed that in both mouse and human CML stem cells, SIRT1 was able to reduce oxidative phosphorylation. The research can also be extended to other hematological malignancies such as acute myeloid leukemia, myeloproliferative neoplasms, and myelodysplastic syndrome, according to the study.

"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. This raises the possibility of developing improved strategies to target kinase-independent metabolic alterations," Bhatia said.

Reference

Abraham A, Qiu S, Chacko BK, et al. SIRT1 regulates metabolism and leukemogenic potential in CML stem cells. J Clin Invest. 2019;130:2685-2701. doi: 10.1172/JCI127080.