CBFB-MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia

A. Mandoli, A. A. Singh, P. W.T.C. Jansen, A. T.J. Wierenga, H. Riahi, G. Franci, K. Prange, S. Saeed, E. Vellenga, M. Vermeulen, H. G. Stunnenberg, J. H.A. Martens

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

68 Citaten (Scopus)

Samenvatting

Different mechanisms for CBFβ-MYH11 function in acute myeloid leukemia with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBFβ-MYH11-binding site analysis and quantitative interaction proteomics, we found that CBFβ-MYH11 localizes to RUNX1 occupied promoters, where it interacts with TAL1, FLI1 and TBP-associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the coregulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knockdown, a small subset of the CBFβ-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBFβ-MYH11 target genes, including genes implicated in hematopoietic stem cell self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and repressed upon fusion protein knockdown. Together these results suggest an essential role for CBFβ-MYH11 in regulating the expression of genes involved in maintaining a stem cell phenotype.

Originele taal-2Engels
Pagina's (van-tot)770-778
Aantal pagina's9
TijdschriftLeukemia
Volume28
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - apr. 2014
Extern gepubliceerdJa

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