Major finding: SIRT1 is overexpressed in imatinib-resistant CML stem cells.

Mechanism: SIRT1 prevents apoptosis by deacetylating and inactivating p53.

Impact: Efficient elimination of CML stem cells may prevent disease recurrence.

Tyrosine kinase inhibitors (TKI) that target BCR–ABL are highly effective in inducing remissions in patients with chronic myelogenous leukemia (CML), but incomplete elimination of quiescent CML leukemic stem cells by TKIs contributes to disease recurrence after cessation of treatment. Because previous studies have shown that the histone deacetylase sirtuin 1 (SIRT1) maintains stem cell self-renewal and is elevated in CML blast crisis cell lines, Li and colleagues evaluated the role of SIRT1 in promoting CML stem cell survival and TKI resistance. SIRT1 expression was significantly elevated in CML stem cells compared with normal cord blood or peripheral blood stem cells, and inhibition of SIRT1 with either short-hairpin RNA or the small-molecule inhibitor tenovin-6 (TV-6) selectively blocked the proliferation and survival of leukemic stem cells. In addition, combining TV-6 and imatinib increased apoptosis of leukemic stem cells—even those that had been isolated from imatinib-refractory CML patients—and impaired engraftment of CML stem cells in vivo more than either agent did alone. To evaluate the mechanistic effects of SIRT1 inhibition, the authors assessed the acetylation status of p53, a key nonhistone SIRT1 target, and found that inhibition of SIRT1 increased p53 acetylation and transcriptional activity. Furthermore, p53 acetylation was required for the increased apoptosis of CML stem cells following SIRT1 inhibition. These findings reveal a critical role for SIRT1 in the maintenance of CML stem cell growth and survival and suggest an approach for targeting the TKI-resistant leukemic stem cell population that prevents lasting remissions or cures even when BCR–ABL is effectively inhibited.

Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T, et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012;21:266–81.