Identification of a Region Which Directs the Monocytic Activity of the Colony-Stimulating Factor 1 (Macrophage Colony-Stimulating Factor) Receptor Promoter and Binds PEBP2/CBF (AML1)

Zhang, D E; Fujioka, Kenta; Hetherington, Christopher J.; Shapiro, LH; Chen, H M; Look, A. Thomas; Tenen, Daniel G.

doi:10.1128/mcb.14.12.8085-8095.1994

Cited by 21 publications

(8 citation statements)

References 19 publications

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“…The PU.1 site at −173 bp, that is also present at a similar position in the mouse gene, displays an altered DMS reactivity in both undifferentiated and differentiated HL60 cells, as well as primary macrophages. This also holds true for the AML1 site at −196 bp, which is absent in the mouse gene, thus validating previously obtained in vitro results (Zhang et al ., 1994). The extent of protection is identical between the cells, confirming our results from the murine c‐fms gene that saw no difference in promoter occupancy during myeloid precursor maturation (Tagoh et al ., 2002).…”

Section: Resultssupporting

confidence: 92%

“…Both the c-FMS promoter and the c-FMS intronic regulatory region are targets for AML1, but the intronic regulatory regions are the main target for AML1±ETO Previous experiments have demonstrated that the promoter of the human c-FMS gene is regulated by AML1 and is also a target for AML1±ETO (Zhang et al, 1994;Rhoades et al, 1996). Our in vivo footprinting results con®rm the occupancy of the promoter AML1 site in committed myeloid cells.…”

Section: Discussionsupporting

confidence: 74%

“…Previous experiments have demonstrated that the promoter of the human c‐FMS gene is regulated by AML1 and is also a target for AML1–ETO (Zhang et al ., 1994; Rhoades et al ., 1996). Our in vivo footprinting results confirm the occupancy of the promoter AML1 site in committed myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

“…One of the target genes of AML1 that is affected by AML1–ETO expression is the human c‐FMS gene (Zhang et al ., 1994). The c‐FMS gene locus encodes the receptor for colony‐stimulating factor‐1 (CSF‐1R), which is essential for macrophage development in vivo (Dai et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic consequences of AML1-ETO action at the human c-FMS locus

et al. 2003

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Although many leukaemia-associated nuclear oncogenes are well characterized, little is known about the molecular details of how they alter gene expression. Here we examined transcription factor complexes and chromatin structure of the human c-FMS gene in normal and leukaemic cells. We demonstrate by in vivo footprinting and chromatin immunoprecipitation assays that this gene is bound by the transcription factor AML1 (RUNX1). In t(8;21) leukaemic cells expressing the aberrant fusion protein AML1-ETO, we demonstrate that this protein is part of a transcription factor complex binding to extended sequences of the c-FMS intronic regulatory region rather than the promoter. The AML1-ETO complex does not disrupt binding of other transcription factors, indicating that c-FMS is not irreversibly epigenetically silenced. However, AML1-ETO binding correlates with changes in the histone modification pattern and increased association of histone deacetylases. Our experiments provide for the first time a direct insight into the chromatin structure of an AML1-ETO-bound target gene.

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Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic consequences of AML1-ETO action at the human c-FMS locus

et al. 2003

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“…The CSF1R and WNT11 promoters were selected for studying the transcriptional properties of RUNX1::ERG as they have been demonstrated to be direct transcriptional targets of RUNX1 and ERG 75 , 76 , respectively. Promoter sequences ( CSF1R : 501-bp, chr5:149,466,084-149,466,584; WNT11 : 1274-bp, chr11:75,917,366-75,918,639) were cloned into the NanoLuc luciferase reporter vector pNL1.1 (Promega).…”

Section: Methodsmentioning

confidence: 99%

Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia

et al. 2023

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Pediatric acute myeloid leukemia (AML) is an uncommon but aggressive hematological malignancy. The poor outcome is attributed to inadequate prognostic classification and limited treatment options. A thorough understanding on the genetic basis of pediatric AML is important for the development of effective approaches to improve outcomes. Here, by comprehensively profiling fusion genes as well as mutations and copy number changes of 141 myeloid-related genes in 147 pediatric AML patients with subsequent variant functional characterization, we unveil complex mutational patterns of biological relevance and disease mechanisms including MYC deregulation. Also, our findings highlight TP53 alterations as strong adverse prognostic markers in pediatric AML and suggest the core spindle checkpoint kinase BUB1B as a selective dependency in this aggressive subgroup. Collectively, our present study provides detailed genomic characterization revealing not only complexities and mechanistic insights into pediatric AML but also significant risk stratification and therapeutic strategies to tackle the disease.

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RUNX1 regulates promoter activity in the absence of cognate DNA binding motifs

Woodworth,

Hardy,

Taberlay

et al. 2024

J of Cellular Biochemistry

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Runt‐related transcription factor 1 (RUNX1) plays an important role in normal haematopoietic cell development and function, and its function is frequently disrupted in leukaemia. RUNX1 is widely recognised as a sequence‐specific DNA binding factor that recognises the motif 5′‐TG(T/C)GGT‐3′ in promoter and enhancer regions of its target genes. Moreover, RUNX1 fusion proteins, such as RUNX1‐ETO formed by the t(8;21) translocation, retain the ability to recognise and bind to this sequence to elicit atypical gene regulatory effects on bona fide RUNX1 targets. However, our analysis of publicly available RUNX1 chromatin immunoprecipitation sequencing (ChIP‐Seq) data has provided evidence challenging this dogma, revealing that this motif‐specific model of RUNX1 recruitment and function is incomplete. Our analyses revealed that the majority of RUNX1 genomic localisation occurs outside of promoters, that 20% of RUNX1 binding sites lack consensus RUNX motifs, and that binding in the absence of a cognate binding site is more common in promoter regions compared to distal sites. Reporter assays demonstrate that RUNX1 can drive promoter activity in the absence of a recognised DNA binding motif, in contrast to RUNX1‐ETO. RUNX1‐ETO supresses activity when it is recruited to promoters containing a sequence specific motif, while interestingly, it binds but does not repress promoters devoid of a RUNX1 recognition site. These data suggest that RUNX1 regulation of target genes occurs through multiple mechanisms depending on genomic location, the type of regulatory element and mode of recruitment.

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Identification of a Region Which Directs the Monocytic Activity of the Colony-Stimulating Factor 1 (Macrophage Colony-Stimulating Factor) Receptor Promoter and Binds PEBP2/CBF (AML1)

Cited by 21 publications

References 19 publications

Epigenetic consequences of AML1-ETO action at the human c-FMS locus

Epigenetic consequences of AML1-ETO action at the human c-FMS locus

Deep genomic characterization highlights complexities and prognostic markers of pediatric acute myeloid leukemia

RUNX1 regulates promoter activity in the absence of cognate DNA binding motifs

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