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...
MOZ-TIF2 is a leukemogenic fusion oncoprotein that confers self-renewal capability to hematopoietic progenitor cells and induces acute myelogenous leukemia (AML) with long latency in bone marrow transplantation assays. Here, we report that FLT3-ITD transforms hematopoietic cells in cooperation with MOZ-TIF2 in vitro and in vivo. Coexpression of FLT3-ITD confers growth factor independent survival/proliferation, shortens disease latency, and results in an increase in the number of leukemic stem cells (LSC). We show that STAT5, a major effector of aberrant FLT3-ITD signal transduction, is both necessary and sufficient for this cooperative effect. In addition, STAT5 signaling is essential for MOZ-TIF2–induced leukemic transformation itself. Lack of STAT5 in fetal liver cells caused rapid differentiation and loss of replating capacity of MOZ-TIF2–transduced cells enriched for LSCs. Furthermore, mice serially transplanted with Stat5−/− MOZ-TIF2 leukemic cells develop AML with longer disease latency and finally incomplete penetrance when compared with mice transplanted with Stat5+/+ MOZ-TIF2 leukemic cells. These data suggest that STAT5AB is required for the self-renewal of LSCs and represents a combined signaling node of FLT3-ITD and MOZ-TIF2 driven leukemogenesis. Therefore, targeting aberrantly activated STAT5 or rewired downstream signaling pathways may be a promising therapeutic option.
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