New Method for Killing Stem Cells May Lead to Leukemia Cure

Blocking the activity of the histone diacetylase enzyme sirtuin 1(SIRT1) was found to increase the activity of the p53 tumor suppressor gene, which was then able to orchestrate the destruction of leukemia stem cells and eliminate the disease.

Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) prolong patient survival but fail to eliminate quiescent leukemia stem cells (LSC) that are resistant to these drugs and eventually cause the cancer to recur.

Previous studies had shown that SIRT1, a histone deacetylase involved in numerous critical cell processes including DNA repair and apoptosis that protect stem cells from stress, was overexpressed in LSCs. Therefore, investigators at the City of Hope National Medical Center (Duarte, CA, USA) examined the effect of blocking SIRT1 activity on these cells.

They reported in the February 14, 2012, issue of the journal Cancer Cell that pharmacological inhibition of SIRT1 or genetically engineered knockdown of its enzymatic activity increased apoptosis in LSC in both chronic phase and blast crisis CML and reduced their growth in vitro and in vivo. The benefits of blocking SIRT1 were enhanced by cotreatment with the BCR-ABL TKI imatinib.

SIRT1 inhibition increased p53 acetylation and transcriptional activity in CML progenitors, and the inhibitory effects of SIRT1 targeting on CML cells depended on p53 expression and acetylation.

“Tyrosine kinase inhibitors do not eliminate leukemia stem cells, which remain a potential source of cancer recurrence,” said senior author Dr. Ravi Bhatia, professor of hematology at the City of Hope National Medical Center. “CML patients need to take tyrosine kinase inhibitor treatment indefinitely, which carries a significant risk of toxicity, lack of compliance, drug resistance, relapse, and associated expense.”

The results of this study suggest that activation of p53 via SIRT1 inhibition may be a viable approach to prevent CML relapse.

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City of Hope National Medical Center