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 June 10, 2019
Citation Information: J Clin Invest. 2019;129(7):2685-2701. https://doi.org/10.1172/JCI127080.
View: Text | PDF
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

×

Figure 9

PGC-1α regulates mitochondrial metabolism and contributes to TKI resistance in CML stem/progenitor cells.

Options: View larger image (or click on image) Download as PowerPoint
PGC-1α regulates mitochondrial metabolism and contributes to TKI resista...
(A) GSEA analysis of gene expression data shows enrichment of the PGC-1α–related gene set in LTHSCs obtained from CML mice compared with normal mice and downregulation in LSK cells from SIRT1-deleted compared with control Cre– CML mice. (B) OCR measurements in c-Kit+ cells from CML mice treated with PGC-1α inhibitor (PGC-1α inh) (SR18292) or vehicle (n = 7 each) for 2 weeks. (C–E) CML mice were treated with vehicle, NIL, PGC-1α inhibitor, or combination (n = 7–8) for 2 weeks. The effect of treatment on WBC (C), neutrophil counts (D), spleen size (E), spleen cellularity (F), splenic LSK cells (G) splenic c-Kit+ cells (H), BM cellularity (I), BM LSK cells (J), and BM c-Kit+ cells (K) are shown. (L) Measurement of OCR in CML CD34+ cells (n = 3) treated with PGC-1α inhibitor or vehicle overnight. (M) Apoptosis of CML CD34+CD38– cells (n = 3) treated with vehicle, PGC-1α inhibitor, NIL, or combination for 72 hours, measured by annexin V labeling. (N) Colony formation from CML CD34+CD38– cells (n = 3) exposed to vehicle, PGC-1α inhibitor, NIL, or combination for 48 hours and plated in methylcellulose progenitor culture. Error bars represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, ordinary 1-way ANOVA (M and N), Kruskal-Wallis 1-way ANOVA (C–K), or 2-way ANOVA (B and L), correcting for multiple comparisons by controlling the FDR using the 2-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli.