Relationship between Radiosensitivity and Nrf2 Target Gene Expression in Human Hematopoietic Stem Cells

2010 ◽  
Vol 174 (2) ◽  
pp. 177-184 ◽  
Author(s):  
Kengo Kato ◽  
Kenji Takahashi ◽  
Satoru Monzen ◽  
Hiroyuki Yamamoto ◽  
Atsushi Maruyama ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Target Gene ◽  
Hematopoietic Stem ◽  
Target Gene Expression ◽  
Nrf2 Target Gene

scholarly journals Graded Smad2/3 Activation Is Converted Directly into Levels of Target Gene Expression in Embryonic Stem Cells

PLoS ONE ◽  
2009 ◽  
Vol 4 (1) ◽  
pp. e4268 ◽  
Author(s):  
Marcela Guzman-Ayala ◽  
Kian Leong Lee ◽  
Konstantinos J. Mavrakis ◽  
Paraskevi Goggolidou ◽  
Dominic P. Norris ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Target Gene ◽  
Embryonic Stem ◽  
Target Gene Expression

scholarly journals A highly efficient reporter system for identifying and characterizing in vitro expanded hematopoietic stem cells

2021 ◽  
Author(s):  
James Lok Chi Che ◽  
Daniel Bode ◽  
Iwo Kucinski ◽  
Alyssa H Cull ◽  
Fiona Bain ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Gene Expression Signature ◽  
The Body ◽  
Molecular Profile ◽  
Functional Screening ◽  
Hematopoietic Stem ◽  
Wide Range ◽  
Single Clone

Hematopoietic stem cells (HSCs) cultured outside the body are the fundamental component of a wide range of cellular and gene therapies. Recent efforts have achieved more than 200-fold expansion of functional HSCs, but their molecular characterization has not been possible due to the substantial majority of cells being non-HSCs and single cell-initiated cultures displaying substantial clone-to-clone variability. Using the Fgd5 reporter mouse in combination with the EPCR surface marker, we report exclusive identification of HSCs from non-HSCs in expansion cultures. Linking single clone functional transplantation data with single clone gene expression profiling, we show that the molecular profile of expanded HSCs is similar to actively cycling fetal liver HSCs and shares a gene expression signature with functional HSCs from all sources, including Prdm16, Fstl1 and Palld. This new tool can now be applied to a wide-range of functional screening and molecular experiments previously not possible due to limited HSC numbers.

scholarly journals Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells

2010 ◽  
Vol 10 (1) ◽  
pp. 12 ◽  
Author(s):  
Leilei Tang ◽  
Saskia M Bergevoet ◽  
Christian Gilissen ◽  
Theo de Witte ◽  
Joop H Jansen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Gene Expression Profile ◽  
Abc Transporter ◽  
Expression Profile ◽  
Transporter Gene ◽  
Hematopoietic Stem

Comparative gene expression analysis of zebrafish and mammals identifies common regulators in hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. e1-e9 ◽  
Author(s):  
Isao Kobayashi ◽  
Hiromasa Ono ◽  
Tadaaki Moritomo ◽  
Koichiro Kano ◽  
Teruyuki Nakanishi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Side Population ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Junction ◽  
Hematopoietic Stem

Abstract Hematopoiesis in teleost fish is maintained in the kidney. We previously reported that Hoechst dye efflux activity of hematopoietic stem cells (HSCs) is highly conserved in vertebrates, and that Hoechst can be used to purify HSCs from teleost kidneys. Regulatory molecules that are strongly associated with HSC activity may also be conserved in vertebrates. In this study, we identified evolutionarily conserved molecular components in HSCs by comparing the gene expression profiles of zebrafish, murine, and human HSCs. Microarray data of zebrafish kidney side population cells (zSPs) showed that genes involved in cell junction and signal transduction tended to be up-regulated in zSPs, whereas genes involved in DNA replication tended to be down-regulated. These properties of zSPs were similar to those of mammalian HSCs. Overlapping gene expression analysis showed that 40 genes were commonly up-regulated in these 3 HSCs. Some of these genes, such as egr1, gata2, and id1, have been previously implicated in the regulation of HSCs. In situ hybridization in zebrafish kidney revealed that expression domains of egr1, gata2, and id1 overlapped with that of abcg2a, a marker for zSPs. These results suggest that the overlapping genes identified in this study are regulated in HSCs and play important roles in their functions.

scholarly journals Hyperglycemia induces abnormal gene expression in hematopoietic stem cells and their progeny in diabetic neuropathy

FEBS Letters ◽  
2014 ◽  
Vol 588 (6) ◽  
pp. 1080-1086 ◽  
Author(s):  
Miwako Katagi ◽  
Tomoya Terashima ◽  
Junko Okano ◽  
Hiroshi Urabe ◽  
Yuki Nakae ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Diabetic Neuropathy ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

MicroRNA-29a Is An Oncogene in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 683-683
Author(s):  
Christopher Y. Park ◽  
Yoon-Chi Han ◽  
Govind Bhagat ◽  
Jian-Bing Fan ◽  
Irving L Weissman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Mirna Expression ◽  
Myeloid Leukemia ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract microRNAs (miRNAs) are short, non-protein encoding RNAs that bind to the 3′UTR’s of target mRNAs and negatively regulate gene expression by facilitating mRNA degradation or translational inhibition. Aberrant miRNA expression is well-documented in both solid and hematopoietic malignancies, and a number of recent miRNA profiling studies have identified miRNAs associated with specific human acute myeloid leukemia (AML) cytogenetic groups as well as miRNAs that may prognosticate clinical outcomes in AML patients. Unfortunately, these studies do not directly address the functional role of miRNAs in AML. In fact, there is no direct functional evidence that miRNAs are required for AML development or maintenance. Herein, we report on our recent efforts to elucidate the role of miRNAs in AML stem cells. miRNA expression profiling of AML stem cells and their normal counterparts, hematopoietic stem cells (HSC) and committed progenitors, reveals that miR-29a is highly expressed in human hematopoietic stem cells (HSC) and human AML relative to normal committed progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors is sufficient to induce a myeloproliferative disorder (MPD) that progresses to AML. During the MPD phase of the disease, miR-29a alters the composition of committed myeloid progenitors, significantly expedites cell cycle progression, and promotes proliferation of hematopoietic progenitors at the level of the multipotent progenitor (MPP). These changes are manifested pathologically by marked granulocytic and megakaryocytic hyperplasia with hepatosplenomegaly. Mice with miR-29a-induced MPD uniformly progress to an AML that contains a leukemia stem cell (LSC) population that can serially transplant disease with as few as 20 purified LSC. Gene expression analysis reveals multiple tumor suppressors and cell cycle regulators downregulated in miR-29a expressing cells compared to wild type. We have demonstrated that one of these genes, Hbp1, is a bona fide miR-29a target, but knockdown of Hbp1 in vivo does not recapitulate the miR-29a phenotype. These data indicate that additional genes are required for miR-29a’s leukemogenic activity. In summary, our data demonstrate that miR-29a regulates early events in normal hematopoiesis and promotes myeloid differentiation and expansion. Moreover, they establish that misexpression of a single miRNA is sufficient to drive leukemogenesis, suggesting that therapeutic targeting of miRNAs may be an effective means of treating myeloid leukemias.

Epigenetic Effects of IDH1/IDH2 Mutations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-33-SCI-33 ◽  
Author(s):  
Ari M. Melnick ◽  
Ross L Levine ◽  
Maria E Figueroa ◽  
Craig B. Thompson ◽  
Omar Abdel-Wahab
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Malignant Transformation ◽  
Covalent Modification ◽  
Specific Gene ◽  
Gene Promoters ◽  
Loss Of Function ◽  
Hematopoietic Stem

Abstract Abstract SCI-33 Epigenetic deregulation of gene expression through aberrant DNA methylation or histone modification plays an important role in the malignant transformation of hematopoietic cells. In particular, acute myeloid leukemias (AMLs) can be classified according to epigenetic signatures affecting DNA methylation or histone modifications affecting specific gene sets. Heterozygous somatic mutations in the loci encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in ∼20% of AMLs and are accompanied by global DNA hypermethylation and hypermethylation and silencing of a number of specific gene promoters. IDH1/2 mutations are almost completely mutually exclusive with somatic loss-of-function mutations in TET2, which hydroxylates methylcytosine (mCpG). DNA hydroxymethylation can function as an intermediate step in mCpG demethylation. TET2 mutant de novo AMLs also display global and promoter specific hypermethylation partially overlapping with IDH1/2 mutant cases. Mutations in the IDH1/2 loci result in a neomorphic enzyme that generates the aberrant oncometabolite 2-hydroxyglutarate (2HG) using α-ketoglutarate (αKG) as a substrate. 2HG can disrupt the activity of enzymes that use αKG as a cofactor, including TET2 and the jumonji family of histone demethylases. Expression of mutant IDH isoforms inhibits TET2 hydroxymethylation and jumonji histone demethylase functions. IDH and TET2 mutant AMLs accordingly exhibit reduced levels of hydroxymethylcytosine and a trend towards increased histone methylation. Mutant IDH or TET2 loss of function causes differentiation blockade and expansion of hematopoietic stem cells and TET2 knockout results in a myeloproliferative phenotype in mice. Hydroxymethylcytosine is in abundance in hematopoietic stem cells and displays specific distribution patterns, yet the function of this covalent modification is not fully understood. Recent data link TET2 with the function of cytosine deaminases as a pathway towards DNA demethylation, which has implications as well for B cell lymphomas and CML lymphoid blast crisis, which are linked with the actions of activation induced cytosine deaminase. Altogether, the available data implicate mutations in IDH1/2 and TET2 in promoting malignant transformation in several tissues, by disrupting epigenomics programming and altering gene expression patterning. Disclosures: Thompson: Agios Pharmaceuticals: Consultancy.

Conditional Expression of a Leukemogenic Fusion Oncogene in Murine Hematopoietic Stem Cells Results in Highly Invasive AML with Origin-Related Genetic Signatures of Prognostic Significance for the Human Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 779-779
Author(s):  
Vaia Stavropoulou ◽  
Susanne Kaspar ◽  
Laurent Brault ◽  
Sabine Juge ◽  
Alexander Tzankov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Overall Survival ◽  
Drug Resistance ◽  
Cell Migration ◽  
Hematopoietic Stem Cells ◽  
Genetic Alterations ◽  
Hematopoietic Stem ◽  
Genetic Signatures ◽  
The Impact

Abstract Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease. Chromosomal translocations causing fusions of the Mixed Lineage Leukemia (MLL) gene are associated with pediatric and adult de novo and therapy-related acute leukemia that are characterized by variable disease outcome. To date, only a limited number of genetic lesions have been implicated in AML disease variability. To address the impact of cellular origin on disease heterogeneity of AMLs, we studied AMLs originating from long-term hematopoietic stem cells (LT-HSCs) and more committed progenitors using a newly established inducible “iMLL-AF9” transgenic mouse model for the t(9:11)(p22;q23) translocation associated MLL-AF9 oncogene. Ex vivo immortalized cells displayed several origin-related growth and drug resistance characteristics and gene expression signatures. Only iMLL-AF9 expressing LT-HSCs formed novel, particularly dispersed colonies, expanded in lineage restrictive stem cell medium and were resistant to genotoxic stress. iMLL-AF9 induction in vivo resulted in fully reversible myelo-monoblastic AML in all animals. Intriguingly, induction of iMLL-AF9 in LT-HSCs caused a particularly aggressive AML phenotype in 15% of recipient mice while the remainder LT-HSCs, as well as short-term HSCs, common myeloid and granulocyte macrophage progenitors induced a more moderate AML. The aggressive LT-HSC-derived AMLs were all characterized by a drastically shorter latency (37 versus 72 days median latency), higher white blood counts, increased invasion capacity and chemo-resistance of leukemic blast, and were associated with expression of genes previously implicated in cell migration, invasion, inflammation and the epithelial-mesenchymal transition (EMT) of solid cancers. shRNA based knock-down experiments demonstrated functional importance of selected candidate genes in cell migration and invasion. Importantly, comparative gene expression analyses between mouse and human revealed that among the genes associated with aggressive AMLs in mice, elevated expression of 66, 11 and 40 human orthologous genes was significantly associated with poor overall survival of t(9;11) (n=21), 11q23-lesion positive, (n=54) and all AMLs (n=662) (p<0.05). Collectively, our data indicates that expression of MLL-AF9 in HSCs results in a particularly aggressive disease driven by expression of common MLL targets and origin-dependent targets previously associated with migration, invasion and EMT of aggressive solid cancers. Remarkably, origin-related genetic signatures associated with the aggressive murine disease revealed a large number of novel MLL-AF9 fusion targets and many highly significant genetic prognostic markers for the overall survival in human AML irrespective of the underlying genetic alterations. Our data experimentally support the previously disputed theory that human AML may also arise from stem and/or oligo-potent progenitors contributing thus to the great heterogeneity of AML including drug resistance and post therapy relapse. Validation of the novel identified target genes in a broader spectrum of human leukemia will facilitate the design of accurate personalized therapeutic interventions. Disclosures No relevant conflicts of interest to declare.

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