SIRT1 regulates metabolism and leukemogenic potential in CML stem cells

Abraham, Ajay; Qiu, Shaowei; Chacko, Balu K.; Li, Hui; Paterson, Andrew J.; He, Jianbo; Agarwal, Puneet; Shah, Mansi; Welner, Robert S.; Darley‐Usmar, Victor; Bhatia, Smita

doi:10.1172/jci127080

Cited by 63 publications

(67 citation statements)

References 51 publications

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“…Accordingly, two recent reports focusing on CML stem cell metabolism confirmed this oxidative phenotype, fueled by fatty acid oxidation [80], and driven by a SIRT1/PGC1-α signaling axis [81]. Importantly, targeting this metabolism, either with a specific agent (tigecycline) or a SIRT1 knockout led to the impairment of CML stem cell functions, showing synergistic interaction with tyrosine kinase inhibitors [80,81].…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 91%

“…Authors found a peculiar pattern of expression, with an upregulation of mitochondrial respiratory chain complex 1 and 2, and a downregulation of complex 3, giving rise to a defective OXPHOS and a consequent production of ROS [79]. Accordingly, two recent reports focusing on CML stem cell metabolism confirmed this oxidative phenotype, fueled by fatty acid oxidation [80], and driven by a SIRT1/PGC1-α signaling axis [81]. Importantly, targeting this metabolism, either with a specific agent (tigecycline) or a SIRT1 knockout led to the impairment of CML stem cell functions, showing synergistic interaction with tyrosine kinase inhibitors [80,81].…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 97%

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mTOR Regulation of Metabolism in Hematologic Malignancies

Mirabilii

Ricciardi

Tafuri

2020

Cells

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Neoplastic cells rewire their metabolism, acquiring a selective advantage over normal cells and a protection from therapeutic agents. The mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase involved in a variety of cellular activities, including the control of metabolic processes. mTOR is hyperactivated in a large number of tumor types, and among them, in many hematologic malignancies. In this article, we summarized the evidence from the literature that describes a central role for mTOR in the acquisition of new metabolic phenotypes for different hematologic malignancies, in concert with other metabolic modulators (AMPK, HIF1α) and microenvironmental stimuli, and shows how these features can be targeted for therapeutic purposes.

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Section: Chronic Myeloid Leukemiamentioning

confidence: 91%

Section: Chronic Myeloid Leukemiamentioning

confidence: 97%

mTOR Regulation of Metabolism in Hematologic Malignancies

Mirabilii

Ricciardi

Tafuri

2020

Cells

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“…Indeed, there is ample evidence to support dysregulated expression of epigenetic regulators as a mechanism underlying epigenetic re-patterning in CP-CML (reviewed elsewhere 144 ), given that most patients lack mutations other than BCR-ABL1. Predictably, there are functional consequences arising from these epigenetic changes: for example, up-regulation of self-renewal by the HOXA (AML) 88,145 or WNT-β-catenin (CP-CML) 146,147 pathways, blocking differentiation by GATA2-driven transcriptional programmes (AML) 131 , or upregulation of mitochondrial metabolism (CP-CML) 148 . However, epigenetic changes also have other functional consequences in LSCs, including repression of apoptosis 93,144 .…”

Section: [H1] Origins and Evolution Of Lscsmentioning

confidence: 99%

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

2020

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For two decades, leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) have been advanced paradigms for the cancer stem cell field. In CML, the acquisition of the fusion tyrosine kinase BCR-ABL1 in a hematopoietic stem cell (HSC) drives its transformation to become a LSC. In AML, LSCs can arise from multiple cell types through the activity of a number of oncogenic drivers and pre-leukemic events-adding further layers of context and genetic and cellular heterogeneity to AML LSCs that is not observed in most cases of CML. Furthermore, LSCs from both AML and CML can be refractory to standardof-care therapies and persist in patients, diversify clonally, and serve as reservoirs to drive relapse, recurrence or progression to more aggressive forms. Despite these complexities, LSCs in both diseases share biological features, making them distinct from other CML or AML progenitor cells and from normal HSCs. These features may represent Achilles' heels against which novel therapies can be developed. Here, we

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“…Notably, among the top-ranked gene list that was upregulated in therapy exposed samples, we focused on the gene encoding SIRT1, a histone deacetylase involved in numerous processes, including self-renewal and stemness maintenance and with particular functions in bioenergetic metabolism [21]. To test the survival dependency of resistant clones on SIRT1, we applied highly selective SIRT1 inhibitors TV-6 and Selisistat (EX 527), findings that PC9 (Figure 1G) and HCC827 (Figure 1H) T20 cells showed higher sensitivity to these inhibitors as compared with parental cells.…”

Section: Resultsmentioning

confidence: 99%

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma

Sun

Liu

et al. 2020

Neoplasia

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Lung adenocarcinoma (LAD) is a human malignancy successfully treated with the tyrosine kinase inhibitor (TKI) gefitinib; however, the enrichment of therapy resistant cancer stem cells (CSCs) in such patients is assumed to be a source of treatment failure. Evaluation of LAD cell populations treated with the TKI inhibitor gefitinib identified unique aspects of a subpopulation of tumor cells exhibiting stem-like properties and mitochondria-specific metabolic features along with their reliance on sirtuin 1 (SIRT1) for survival advantage. This addiction to bioenergetic metabolism in LAD treated with EGFR-targeted therapy suggests that mitochondrial targeting should be synthetically lethal using established cytotoxic therapies. Accordingly, loss of the phenotype present in resistant CSC clones either by targeting the energy metabolism with tigecycline, a mitochondrial DNA-translation inhibitor, or tenovin-6 (TV-6), a SIRT1 inhibitor, inhibited their dependency on mitochondrial oxidative phosphorylation (mtOXPHOS) and sensitized them for a more pronounced and long-lasting TKI therapeutic effect. The results specifically demonstrated that combined therapy with TV-6 and gefitinib resulted in tumor regression in xenograft mouse models, whereas administration of a single agent showed no such efficacy. Importantly, combined treatment with TV-6 also decreased the effective dose of gefitinib necessary for treatment response. Clinical analysis demonstrated that high-profile SIRT1 and mtOXPHOS proteins were associated with recurrence and poor prognosis in LAD patients. These observations support the CSC hypothesis for cancer relapse and advocate use of mitochondria-targeting inhibitors as part of combinatorial therapy in a variety of clinical settings, as well as for reducing first-line TKI dosage in LAD patients.

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SIRT1 regulates metabolism and leukemogenic potential in CML stem cells

Cited by 63 publications

References 51 publications

mTOR Regulation of Metabolism in Hematologic Malignancies

mTOR Regulation of Metabolism in Hematologic Malignancies

The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML

Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma

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