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 4

UBC ERT2-Cre–mediated SIRT1 deletion inhibits CML hematopoiesis.

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UBC ERT2-Cre–mediated SIRT1 deletion inhibits CML hematopoiesis. (A) Exp...
(A) Experimental strategy for studying the effect of SIRT1 deletion on CML development using UBC ERT2-Cre/SIRT1fl/fl/BCR-ABL model: BM cells from either SCL-tTA-BCR-ABL UBC-ERT2-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 tamoxifen (TAM) injection (1 mg/mouse) starting at 4 weeks after transplant, followed by tetracycline withdrawal to induce BCR-ABL expression. Mice were sacrificed and analyzed 8 weeks after CML induction and SIRT1 deletion (n = 10 each). (B–D) Effect of SIRT1 deletion on blood parameters, including WBC (B), neutrophil counts (C), and donor Gr1+Mac1+ myeloid cell frequencies determined by flow cytometry (D) (n = 6–7). Effect of SIRT1 deletion on spleen weight (E), spleen cellularity (F), BM cellularity (G), and frequencies of donor B cells, myeloid cells, and T cells in BM by flow cytometry (H) at 8 weeks. (I–M) Effect of SIRT1 deletion on absolute numbers of BM LTHSCs (I), STHSCs (J), MPPs (K), GMPs (L), and MEPs (M). (N) Cell cycle analysis on LTHSC populations from BM using DAPI and KI67 labeling. Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, t test.