Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis

Wagner, Wolfgang; Ansorge, Alexandra; Wirkner, Ute; Eckstein, Volker; Schwager, Christian; Blake, Jonathon; Miesala, Katrin; Selig, Jan; Saffrich, Rainer; Ansorge, Wilhelm; Ho, Anthony D.

doi:10.1182/blood-2003-10-3423

Cited by 122 publications

(140 citation statements)

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“…For example, it occurred at the PROM1 (prominin-1/CD133) gene (Fig. 1B), which encodes a defining antigen of hematopoietic stem cells and is purported to play a role in asymmetric cell divisions in adult stem cells (Wagner et al 2004;Toren et al 2005), and HOXA7, HOXA9, HOXA10 ( Fig. 2A), whose overexpression are hallmarks of ALLs carrying the t(4;11) chromosome translocation (Rozovskaia et al 2001(Rozovskaia et al , 2003Armstrong et al 2002;Yeoh et al 2002;Ferrando et al 2003).…”

Section: Identification Of Mll-af4-occupied Regions Of the Genome In mentioning

confidence: 99%

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Guenther¹,

Lawton²,

Rozovskaia³

et al. 2008

Genes Dev.

251

263

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Mixed-lineage leukemia (MLL) fusion proteins are potent inducers of leukemia, but how these proteins generate aberrant gene expression programs is poorly understood. Here we show that the MLL-AF4 fusion protein occupies developmental regulatory genes important for hematopoietic stem cell identity and self-renewal in human leukemia cells. These MLL-AF4-bound regions have grossly altered chromatin structure, with histone modifications catalyzed by trithorax group proteins and DOT1 extending across large domains. Our results define direct targets of the MLL fusion protein, reveal the global role of epigenetic misregulation in leukemia, and identify new targets for therapeutic intervention in cancer.Supplemental material is available at http://www.genesdev.org.Received September 16, 2008; revised version accepted November 4, 2008. Chromosomal translocations involving the mixed-lineage leukemia gene (MLL) are a frequent occurrence in human acute leukemias of both children and adults (Eguchi et al. 2005). In over half of all infant acute leukemias, the MLL protein fuses to one of >50 identified partner genes, resulting in a MLL fusion protein that acts as a potent oncogene (Krivtsov and Armstrong 2007). While extensive gene expression signatures have been determined for primary human leukemia samples (Armstrong et al. 2002;Yeoh et al. 2002;Ferrando et al. 2003;Ross et al. 2003;Rozovskaia et al. 2003;Haferlach et al. 2005), the direct genomic targets of MLL fusion proteins remain unknown. This information is essential to determine how MLL fusion proteins impose oncogenic transcriptional programs and to identify targets for therapeutic intervention in human disease.Distinct chromatin-modifying complexes and histone modifications are associated with distinct phases of transcription (Li et al. 2007). The trithorax group proteins, including MLL, catalyze histone H3-Lys-4 trimethyl (H3K4me3) modifications at the start sites of transcriptionally engaged genes (Ruthenburg et al. 2007). These H3K4me3-modified regions are largely constrained to the transcription start site regions of genes that are transcriptionally initiated, but not necessarily fully transcribed (Bernstein et al. 2006;Barski et al. 2007;Guenther et al. 2007). As a gene becomes fully transcribed, elongating RNA Polymerase II (Pol II) molecules proceed through gene coding regions along with associated elongation factors including DOT1, which catalyzes dimethylation of histone H3-Lys-79 (H3K79me2) (Li et al. 2007). Physical interactions between the most common MLL partner proteins and transcriptional elongation components suggest that defects in H3K4 and H3K79 methylation might be a key factor in MLL leukemogenesis In order to define the portion of gene regulatory circuitry that is controlled directly by MLL fusion proteins in human leukemia, we determined the binding patterns of an MLL fusion protein and chromatin modifications across the entire human genome. We performed this mapping in leukemic cells harboring the MLL-AF4 fusion gene, because this rearran...

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Section: Identification Of Mll-af4-occupied Regions Of the Genome In mentioning

confidence: 99%

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Guenther¹,

Lawton²,

Rozovskaia³

et al. 2008

Genes Dev.

251

263

View full text Add to dashboard Cite

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“…1,2 Recently, HSCs have been shown to slowly cycle in vivo during steady-state hematopoiesis. [3][4][5][6][7][8][9][10] Self-renewal of HSCs has been tracked in mice by marking HSCs with retroviral vectors. 11 Quantitative studies have also documented HSC expansion following stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Araki

Yoshinaga

Boccuni

et al. 2006

Blood

109

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“…It has not been previously associated with hematopoiesis, although it was detected in DNA-microarray gene expression analysis of the slow-dividing CD133-positive hematopoietic stem cells (38). Different isoforms of ERG are expressed by alternative splicing and the utilization of different 5V UTRs.…”

Section: Erg In Acute Megakaryoblastic Leukemiamentioning

confidence: 99%

The Proto-Oncogene ERG in Megakaryoblastic Leukemias

et al. 2005

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Aneuploidy is one of the hallmarks of cancer. Acquired additions of chromosome 21 are a common finding in leukemias, suggesting a contributory role to leukemogenesis. About 10% of patients with a germ line trisomy 21 (Down syndrome) are born with transient megakaryoblastic leukemia. We and others have shown acquired mutations in the X chromosome gene GATA1 in all these cases. The gene or genes on chromosome 21 whose overexpression promote the megakaryoblastic phenotype are presently unknown. We propose that ERG, an Ets transcription factor situated on chromosome 21, is one such candidate. We show that ERG is expressed in hematopoietic stem cells, megakaryoblastic cell lines, and in primary leukemic cells from Down syndrome patients. ERG expression is induced upon megakaryocytic differentiation of the erythroleukemia cell lines K562 and UT-7, and forced expression of ERG in K562 cells induces erythroid to megakaryoblastic phenotypic switch. We also show that ERG activates the gpIb megakaryocytic promoter and binds the gpIIb promoter in vivo. Furthermore, both ERG and ETS2 bind in vivo the hematopoietic enhancer of SCL/ TAL1, a key regulator of hematopoietic stem cell and megakaryocytic development. We propose that trisomy 21 facilitates the occurrence of megakaryoblastic leukemias through a shift toward the megakaryoblastic lineage caused by the excess expression of ERG, and possibly by other chromosome 21 genes, such as RUNX1 and ETS2, in hematopoietic progenitor cells, coupled with a differentiation arrest caused by the acquisition of mutations in GATA1. (Cancer Res 2005; 65(17): 7596-602)

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Molecular evidence for stem cell function of the slow-dividing fraction among human hematopoietic progenitor cells by genome-wide analysis

Cited by 122 publications

References 62 publications

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia

Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

The Proto-Oncogene ERG in Megakaryoblastic Leukemias

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