SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia

Abstract

Key Points• SIRT1 is highly expressed in subsets of patients with acute myeloid leukemia harboring activating mutations in signaling pathways and is regulated at the protein levels.• Targeting SIRT1 sensitizes leukemic blast to tyrosine kinase inhibitor treatment or chemotherapy via restoration of p53 activity.SIRT1 is an important regulator of cellular stress response and genomic integrity. Its role in tumorigenesis is controversial. Whereas sirtuin 1 (SIRT1) can act as a tumor suppressor in some solid tumors, increased expression has been demonstrated in many cancers, including hematologic malignancies. In chronic myeloid leukemia, SIRT1 promoted leukemia development, and targeting SIRT1 sensitized chronic myeloid leukemia progenitors to tyrosine kinase inhibitor treatment. In this study, we investigated the role of SIRT1 in acute myeloid leukemia (AML). We show that SIRT1 protein, but not RNA levels, is overexpressed in AML samples harboring activating mutations in signaling pathways. In FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) 1-cells protein, expression of SIRT1 is regulated by FLT3 kinase activity. In addition, SIRT1 function is modulated via the ATM-DBC1-SIRT1 axis in a FLT3-ITD-dependent manner. In murine leukemia models driven by MLL-AF9 or AML1-ETO coexpressing FLT3-ITD, SIRT1 acts as a safeguard to counteract oncogene-induced stress, and leukemic blasts become dependent on SIRT1 activity. Pharmacologic targeting or RNAi-mediated knockdown of SIRT1 inhibited cell growth and sensitized AML cells to tyrosine kinase inhibitor treatment and chemotherapy. This effect was a result of the restoration of p53 activity. Our data suggest that targeting SIRT1 represents an attractive therapeutic strategy to overcome primary resistance in defined subsets of patients with AML. (Blood. 2014;124(1):121-133) IntroductionSirtuins, also referred to as class III histone deacetylases, are NAD 1 -dependent protein deacetylases. The founding member, silent information regulator 2 (Sir2), was originally identified in Saccharomyces cerevisiae and has been linked to longevity.1 Mammalian sirtuin 1 (SIRT1) plays an important role in the regulation of gene expression and the maintenance of genomic integrity. For example, SIRT1 deacetylates histones H4K16Ac and H3K9Ac and promotes H3K9 trimethylation, resulting in the formation of heterochromatin and gene silencing under conditions of oxidative stress. 2,3 Further, SIRT1 contributes to the regulation of DNA damage response (DDR) and repair. Upon an ataxia teleangiectasia mutated (ATM)-dependent recruitment to double-strand breaks, SIRT1 induces epigenetic changes, participates in chromatin remodeling, and directly modulates several nonhistone proteins involved in DDR. [4][5][6][7] In addition, SIRT1 plays an important role in integrating and coordinating cellular stress response. Sirt1 deacetylates p53 at lysine 382 and reduces its transcriptional activity, followed by the loss of p53-dependent apoptosis in response to cell damage. 8,9 Further, SIRT1 p...

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…Deacetylated p53 and SIRT1 overexpression can be detected by immunoblotting. 74,84 In cases of non-SIRT1-mediated deacetylation, HDAC and MDM2 inhibitors might be beneficial. wtp53 cytoplasmic sequestration, confirmed by immunocytochemical staining, 114 can be reversed by CRM1 inhibition.…”

Recently Emerging Signaling Landscape of Ataxia-Telangiectasia Mutated (ATM) Kinase

“…Protein expression of SIRT1 is overexpressed in Ammad Ahmad Farooqi et al FLT3-ITD+-cells and regulated by FLT3 kinase activity. Genetic or chemical inhibition of SIRT1 remarkably enhanced p53 mediated apoptosis (Sasca et al, 2014). It has recently been persuasively revealed that ATM was not induced in irradiated HER2 silenced MCF-7 breast cancer cells (Yan et al, 2014).…”

SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae))

“…SIRT1 protein is stabilized by USP22, a deubiquitinase that is induced by c-MYC in FLT-ITD AML cells (Li et al, 2014). In addition, SIRT1 activity is further regulated by ATM-DBC1 in a FLT-ITD dependent manner (Sasca et al, 2014). Inhibition of SIRT1 sensitizes FLT-ITD AML stem/progenitor cells to tyrosine kinase inhibitor treatment, and may help improve management of this category of AML.…”

“…SIRT1 protein expression is more consistently increased in AML samples, particularly those harboring FLT-ITD alteration. The change of SIRT1 mRNA is less consistent in certain AML subcategories from one to another study (Sasca et al, 2014;Li et al, 2014). Prognosis AML with FLT-ITD mutation has poor prognosis.…”