SIRT1 regulates metabolism and leukemogenic potential in CML stem cells
Ajay Abraham, … , Victor M. Darley-Usmar, Ravi Bhatia
Ajay Abraham, … , Victor M. Darley-Usmar, Ravi Bhatia
Published July 1, 2019; First published June 10, 2019
Citation Information: J Clin Invest. 2019;129(7):2685-2701. https://doi.org/10.1172/JCI127080.
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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 3

Mx1-Cre–mediated SIRT1 deletion inhibits CML stem and progenitor cells.

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Mx1-Cre–mediated SIRT1 deletion inhibits CML stem and progenitor cells. ...
(A–E) Effect of SIRT1 deletion on splenic stem and progenitor subpopulations, including LTHSCs (A), STHSCs (B), MPPs (C), GMPs (D), and MEPs (E), at 8 weeks after SIRT1 deletion (n = 6 each). (F–J) Effect of SIRT1 deletion on BM stem and progenitor subpopulations, including LTHSCs (F), STHSCs (G), MPPs (H), GMPs (I). and MEPs (J). Corresponding stem and progenitor cell populations from normal mice are shown for comparison. (K) Experimental strategy for checking long-term repopulating potential of LTHSCs following SIRT1 deletion. Donor LTHSCs (CD45.2) were selected from SIRT1-deleted and control primary recipient mice by flow cytometry and transplanted to sublethally irradiated (800cGy) secondary recipients (200 cells/mouse), together with 500,000 supporting BM cells (CD45.1) (n = 8–9 each). (L–S) Recipient mice were followed with serial blood counts and subsequently analyzed for BM stem and progenitor cells. Peripheral blood WBC counts and frequency of CD45.2 donor cells (M) in secondary recipients are shown. (N–S) Frequency (Freq.) of donor cells, including total CD45.2 (N), LTHSCs (O), STHSCs (P), MPPs (Q), GMPs (R), and MEPs (S) in secondary recipient BM. (T) Kaplan-Meier analysis of survival of SCL-tTA/BCR-ABL Mx1-Cre SIRT1fl/fl mice compared with Cre controls. Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, t test, except Kaplan-Meier analysis.