Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A

Milhem, Mohammed; Mahmud, Nadim; Lavelle, Donald; Araki, Hiroto; DeSimone, Joseph; Saunthararajah, Yogen; Hoffman, Ronald

doi:10.1182/blood-2003-07-2431

Cited by 189 publications

(205 citation statements)

References 41 publications

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“…Very recently, Milhem et al [8] reported that hematopoietic progenitor cells were expanded by a combination treatment of 5-aza-2 0 -deoxycythidine, Trichostatin A (a histone deacetylation inhibitor), and cytokine cocktail (stem cell factor, granulocytemonocyte colony-stimulating factor, interleukin-3, interleukin-6, and erythropoietin). Their observation supported the results in our study.…”

Section: Resultsmentioning

confidence: 99%

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells

et al. 2004

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DNA methylation plays important roles in a wide range of biological phenomena, especially in the embryonic development and tumorigenesis. However, correlations between differentiation and DNA methylation have not been clarified well in each differentiation system. In this study, we focused our attention on regulatory roles of DNA methylation in normal hematopoietic differentiation using a demethylating reagent, 5-azacytidine (5-AzaC). As a source of hematopoietic progenitor cells, we used CD34 + cells prepared from human umbilical cord blood and examined the effects of 5-AzaC on the colony-forming activity and the long-term culture-initiating (LTC-IC) activity of these cells. 5-AzaC treatment increased LTC-IC frequency 1.57-to 2.50-fold as compared to the nontreated control. In parallel to this, immunoblotting analysis showed that the intensity of overall DNA methylation decreased after 5-AzaC treatment. These results indicated the involvement of DNA methylation and demethylation in controlling immaturity of hematopoietic progenitor cells and the usefulness of 5-AzaC for regulating this immaturity. Am.

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Section: Resultsmentioning

confidence: 99%

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells

et al. 2004

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“…It is reasonable to assume that the failures of current cancer therapy are in part due to the failure to target cancer stem cells. HDACi affect the maintenance of stem-cell potential in CD34 + human haematopoietic progenitors in vitro 125 . So far, no study using HDACi (either preclinical or clinical) has addressed the crucial issue of tumour stem-cell sensitivity, which should be clarified as soon as possible to verify the true potential of HDACi in clinical treatment.…”

Section: Perspectivesmentioning

confidence: 99%

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

2006

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| Histone deacetylases (HDACs) are considered to be among the most promising targets in drug development for cancer therapy, and first-generation histone deacetylase inhibitors (HDACi) are currently being tested in phase I/II clinical trials. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. However, several basic aspects are not yet fully understood. Investigating these aspects in the context of what we now understand about HDACi action both in vitro and in vivo will further improve the design of optimized clinical protocols.Histone deacetylases (HDACs) have been intensively scrutinized over the past few years for two main reasons. First, they have been linked mechanistically to the pathogenesis of cancer, as well as several other diseases. Second, small-molecule HDAC inhibitors (HDACi) exist that have the capacity to interfere with HDAC activity and can therefore achieve significant biological effects in preclinical models of cancer. These findings justified the introduction of HDACi into clinical trials. These initial clinical trials have just ended and show encouraging results. At this stage it is crucial to evaluate whether our current knowledge on the mechanisms of tumorigenesis that are linked to HDACs, and on the mechanisms of tumour sensitivity to HDACi, is firm enough to improve the design of further clinical trials. Recent structural and chemical data have emerged that will help in the design of novel HDACi with more desirable properties than the existing ones. However, key areas of investigation that might help to further illuminate the design of successful HDACi-based cancer therapy remain poorly explored. Novel findings indicate that our understanding of how HDACi work will probably change significantly, establishing a new paradigm in the field of intelligent drug design with broad implications for the design of targeted therapies in cancer and possibly other diseases.HDACs: enzymes looking for substrate(s) Four HDAC classes have been identified (FIG. 1a). One of them (class 3 or the so-called sirtuins, from the yeast protein Sir2) constitutes a structurally unrelated, NADdependent subfamily, and will not be considered here; neither will the class 3-specific HDACi, which are less characterized than those for the other classes 1 .An extensive phylogenetic analysis of HDACs has been performed 2,3 . HDACs are members of an ancient enzyme family found in animals, plants, fungi and bacteria. It is thought that HDACs evolved in the absence of histone proteins. Indeed, eukaryotic HDACs can deacetylate non-histone as well as histone substrates, and some HDACs reside in the cytoplasm (where histones are synthesized and acetylated for proper assembly, without the intervention of HDACs) and in mitochondria (where histones are absent).Are HDACs, then, truly HDACs 4 ? We postulate that key HDAC substrates might not be histones, but instead belong to the growing list of acetylated non-histone proteins (FIG. 1b and Supplementary information S1 ...

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“…The use of all-trans retinoic acid, epigenic modification, and copper chelation [25][26][27][28] are all novel methods that may prove useful to allow expansion of the primitive pool of HSC in CB without inducing engraftment defects.…”

Section: Discussionmentioning

confidence: 99%

Generation of functional natural killer and dendritic cells in a human stromal-based serum-free culture system designed for cord blood expansion

Frias

Porada

Crapnell

et al. 2008

Experimental Hematology

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Objective-We have previously reported the ability of a mesenchymal stem cell (MSC)-based serum-free culture system to expand human cord blood (CB) hematopoietic stem cells (HSC) along the myeloid pathway and simultaneously generate a CD7 + CD34 -population. In this study, we investigated the ability of the CD7 + CD34 -population to differentiate into natural killer and dendritic cells.Materials and Methods-CB CD34 + cells were expanded over a MSC layer in serum-free medium supplemented with SCF, bFGF, LIF, and FL for 2 weeks. Cultured cells were harvested and CD7 + CD34 -Lin -cells sorted and plated for two additional weeks in either natural killer (NK)-or dendritic cell (DC)-inductive medium.Results-culture of CD34 + cells for the first 2 weeks in this system resulted in expansion of the stem cell pool and the myeloid component of the graft, and also produced a 58 fold-increase in the CD7 + CD34 -cell population. When sorted CD7 + CD34 -Lin -cells were induced towards a NK phenotype, further expansion was observed during this time in culture, and differentiation was confirmed by cytotoxic activity and by flow cytometry, with cells displaying CD16 and CD56 in the absence of CD3. The generation of DC cells in culture was also verified by observing both the characteristic dendritic morphology and the dendritic phenotypes HLA-DR bright CD123 bright CD11c -and HLA-DR bright CD11c + .Conclusion-These results demonstrate the ability of an ex-vivo culture system to drive the expansion of human CB HSCs while promoting the immune maturation of the graft and the generation of DC and NK cells that could then be utilized for adoptive cancer cellular immunotherapy.

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Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A

Cited by 189 publications

References 41 publications

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Generation of functional natural killer and dendritic cells in a human stromal-based serum-free culture system designed for cord blood expansion

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Modification of hematopoietic stem cell fate by 5aza 2′deoxycytidine and trichostatin A

Cited by 189 publications

References 41 publications

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34+ cells

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34+ cells

Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer

Generation of functional natural killer and dendritic cells in a human stromal-based serum-free culture system designed for cord blood expansion

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Product

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5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells

5‐azacytidine supports the long‐term repopulating activity of cord blood CD34⁺ cells