NAMPT is essential for the G-CSF–induced myeloid differentiation via a NAD+–sirtuin-1–dependent pathway

Skokowa, Julia; Lan, Dan; Thakur, Basant Kumar; Wang, Fei; Gupta, Kshama; Cario, Gunnar; Brechlin, Annette Müller; Schambach, Axel; Hinrichsen, Lars; Meyer, Gustav; Gaestel, Matthias; Stanulla, Martin; Tong, Qiang; Welte, Karl

doi:10.1038/nm.1913

Cited by 198 publications

(120 citation statements)

References 40 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Increased amounts of Nampt in mammalian cells cause upregulation of NAD + . Nampt is a rate-limiting enzyme in the conversion of nicotinamide into NAD + , which is crucial for SIRT1 activation and regulation of transcription; Nampt could co-regulate the sirtuins and other NAD + -dependent processes by (i) lowering the NAM concentration and (ii) boosting NAD + levels in the cytoplasm, nucleus and perhaps even in mitochondria (Skokowa et al 2009;van Gool et al 2009). Nampt which converts nicotinamide (NAM) into NAD + could be the target of resveratrol rather than SIRT1.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activity

Zhang

Zhou

et al. 2009

Life Sciences

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activity

Zhang

Zhou

et al. 2009

Life Sciences

View full text Add to dashboard Cite

“…Recently, we identified nicotinamide phosphoribosyl transferase (NAMPT), also known as pre-B-cell colony-enhancing factor, as an essential enzyme mediating G-CSF-triggered granulopoiesis in healthy persons and in persons with CN. 31 The enzyme NAMPT converts nicotinamide to nicotinamide mononucleotide, which is converted into nicotinamide adenine dinucleotide (NAD ϩ ) by nicotinamide mononucleotide adenylyltransferase in the mammalian biosynthetic pathway. 9 NAD ϩ regulates the transcription and function of sirtuins (SIRTs), which are lysine deacetylases for C/EBP␣ and C/EBP␤.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1

Skokowa

Fobiwe

Lan

et al. 2009

Blood

Self Cite

View full text Add to dashboard Cite

Severe congenital neutropenia (CN) is a heterogeneous disorder of myelopoiesis which follows an autosomal dominant or autosomal recessive pattern of inheritance. Genetic analyses indicate mutations in the ELA2 gene in most patients. We have identified LEF-1 as a decisive transcription factor in granulopoiesis controlling proliferation and granulocytic differentiation by direct activation of its target gene, C/EBPalpha. In patients with CN, the expression of LEF-1 and C/EBPalpha was abrogated in myeloid progenitors leading to maturation arrest of granulopoiesis. In the present study we demonstrated that ELA2 mRNA expression in myeloid progenitors and plasma protein levels of neutrophil elastase (NE) were markedly reduced in patients with CN harboring mutations in either ELA2 or HAX-1 genes. The ELA2 gene promoter is positively regulated by the direct binding of LEF-1 or C/EBPalpha, documenting the role of LEF1 in the diminished ELA2 expression. We found that transduction of hematopoietic cells with LEF-1 cDNA resulted in the up-regulation of ELA2/NE synthesis, whereas inhibition of LEF-1 by shRNA led to a marked reduction in the levels of ELA2/NE. LEF-1 rescue of CD34(+) cells isolated from 2 patients with CN resulted in granulocytic differentiation of the cells which was in line with increased levels of functionally active ELA2/NE.

show abstract

“…Fetal MPs and BM cells from adult mice were processed, expanded, and infected as published previously (Li et al 2005). Culture, transduction on RetroNectin-coated (Takara) plates, and in vitro differentiation of CD34 + -HSPC cells was performed as described (Klein et al 2007;Skokowa et al 2009). The mouse stem cell virus (pMSCV)-based pMSCV-puro (Clontech), pMIGR1 (Pui et al 1999), pMSCV-Puro-IRES-GFP (pLPIG), and pMSCV-Puro-IRES-GFP containing the miR-30 backbone (pLMPIG) vectors were used.…”

Section: Cell Culture and Transductionmentioning

confidence: 99%

miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia

Klusmann¹,

Li²,

Böhmer³

et al. 2010

Genes Dev.

211

208

View full text Add to dashboard Cite

Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.

show abstract

NAMPT is essential for the G-CSF–induced myeloid differentiation via a NAD+–sirtuin-1–dependent pathway

Cited by 198 publications

References 40 publications

Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activity

Resveratrol inhibited Tat-induced HIV-1 LTR transactivation via NAD+-dependent SIRT1 activity

Neutrophil elastase is severely down-regulated in severe congenital neutropenia independent of ELA2 or HAX1 mutations but dependent on LEF-1

miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia

Contact Info

Product

Resources

About