SIRT1 regulates metabolism and leukemogenic potential in CML stem cells
Ajay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, Ravi Bhatia
Ajay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, Ravi Bhatia
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Research Article Hematology Oncology

SIRT1 regulates metabolism and leukemogenic potential in CML stem cells

Abstract

Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1α contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for SIRT1 and downstream signaling mechanisms in altered mitochondrial respiration in CML LSCs.

Authors

Ajay Abraham, Shaowei Qiu, Balu K. Chacko, Hui Li, Andrew Paterson, Jianbo He, Puneet Agarwal, Mansi Shah, Robert Welner, Victor M. Darley-Usmar, Ravi Bhatia

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Figure 2

Mx1-Cre mediated SIRT1 deletion inhibits leukemia development in CML mice.

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Mx1-Cre mediated SIRT1 deletion inhibits leukemia development in CML mic...
(A) Experimental strategy for studying the role of SIRT1 deletion on CML hematopoiesis. BM cells from either BA Mx1-Cre SIRT1fl/fl or Cre– controls (both CD45.2) were transplanted into irradiated (800 cGy) CD45.1 congenic recipients (2 × 106 cells/mouse). Cre-mediated deletion of SIRT1 was induced by pIpC injection starting at 4 weeks after transplant, followed by tetracycline withdrawal to induce BCR-ABL expression. Mice were followed for CML and SIRT1 development and analyzed for BM and spleen stem/progenitors (shown in Figure 3). (B–D) Peripheral blood parameters were evaluated over time after SIRT1 deletion. Results for WBCs (B), neutrophils (C), and Gr1+Mac1+ myeloid cells (D) determined by flow cytometry. (E–I) Effect of SIRT1 deletion on spleen and BM parameters at 8 weeks, including spleen size (E), spleen weight (F), spleen cellularity (G), BM cellularity (H), and frequencies of CD45.2 donor cells, B cells, and myeloid cells by flow cytometry in BM (I) (n = 6 each). Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, t test.