SIRT1 is downregulated during neutrophil differentiation of acute promyelocytic leukaemia cells

Wampfler, Julian; Tschan, Mario P.; Shan, Deborah; Laemmle, Alexander; Leibundgut, Elisabeth Oppliger; Baerlocher, Gabriela M.; Stroka, Deborah; Fey, Martin F.; Britschgi, Christian

doi:10.1111/j.1365-2141.2009.07749.x

Cited by 9 publications

(8 citation statements)

References 11 publications

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“…Less is know about SIRT1 activity in neutrophils. SIRT1 expression is decreased in neutrophils differentiated from acute promyelocytic leukemia cells [36], suggesting that it may be expressed at low levels in this cell type. …”

Section: Discussionmentioning

confidence: 99%

Myeloid Cell Sirtuin-1 Expression Does Not Alter Host Immune Responses to Gram-Negative Endotoxemia or Gram-Positive Bacterial Infection

et al. 2013

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The role of sirtuin-1 (SIRT1) in innate immunity, and in particular the influence of SIRT1 on antimicrobial defense against infection, has yet to be reported but is important to define since SIRT1 inhibitors are being investigated as therapeutic agents in the treatment of cancer, Huntington’s disease, and autoimmune diseases. Given the therapeutic potential of SIRT1 suppression, we sought to characterize the role of SIRT1 in host defense. Utilizing both pharmacologic methods and a genetic knockout, we demonstrate that SIRT1 expression has little influence on macrophage and neutrophil antimicrobial functions. Myeloid SIRT1 expression does not change mortality in gram-negative toxin-induced shock or gram-positive bacteremia, suggesting that therapeutic suppression of SIRT1 may be done safely without suppression of myeloid cell-specific immune responses to severe bacterial infections.

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Section: Discussionmentioning

confidence: 99%

Myeloid Cell Sirtuin-1 Expression Does Not Alter Host Immune Responses to Gram-Negative Endotoxemia or Gram-Positive Bacterial Infection

et al. 2013

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“…The functional importance of this chromatin mark was revealed by the involvement of the modified targets on the TGF-b pathway, which were previously reported to be inhibited by AML1-ETO fusion protein, 39 or of ERK/MAPK, a key pathway in the self-renewal process of hematopoietic stem cells. 40 Among the identified genes, we found novel AML1-ETO target genes previously described to be involved on the hematopoietic development, which repression could be a relevant step in the AML RPS19, a ribosomal protein which silencing decrease the proliferative capacity of hematopoietic progenitors and leads to a defect on erythroid development; 42 SIRT1, downregulated during neutrophil differentiation of acute promyelocytic leukemia cells 43 and CTCF which knockdown inhibited differentiation into erythroid lineage of the K562 cell line. 44 The 264 genes identified as AML1-ETO targets with an increased H3K9me3 were found to be significantly involved in the Wnt/bcatenin and stem cell pluripotency pathways.…”

Section: Discussionmentioning

confidence: 99%

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

et al. 2012

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The AML1-ETO fusion protein, which is present in 10 --15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.Leukemia ( Keywords: AML1-ETO; myeloid leukemia ; histone deacetylation; H3K9me3; Sp1 INTRODUCTIONThe presence of the AML1-ETO fusion protein indicates acute myeloid leukemia (AML) with t(8;21)(q22;q22), which accounts for B10 --15% of all AML cases.1,2 This product is the consequence of a reciprocal translocation that fuses the DNA binding domain of the AML1 transcription factor essential for transcriptional activation of genes involved in normal hematopoiesis in frame with nearly the entire ETO protein, a transcriptional repressor molecule expressed in a variety of tissues.

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“…Successful neutrophil differentiation was assessed by CD11b FACS analysis and CCAAT/enhancer binding protein (CEBPE) as well as colony stimulating factor 3 receptor (CSF3R) qPCR [5,6].…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Inhibition of damage-regulated autophagy modulator-1 (DRAM-1) impairs neutrophil differentiation of NB4 APL cells

Humbert¹,

Mueller²,

Fey³

et al. 2012

Leukemia Research

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SIRT1 is downregulated during neutrophil differentiation of acute promyelocytic leukaemia cells

Cited by 9 publications

References 11 publications

Myeloid Cell Sirtuin-1 Expression Does Not Alter Host Immune Responses to Gram-Negative Endotoxemia or Gram-Positive Bacterial Infection

Myeloid Cell Sirtuin-1 Expression Does Not Alter Host Immune Responses to Gram-Negative Endotoxemia or Gram-Positive Bacterial Infection

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

Inhibition of damage-regulated autophagy modulator-1 (DRAM-1) impairs neutrophil differentiation of NB4 APL cells

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