Journal
ONCOGENE
Volume 35, Issue 15, Pages 1965-1976Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.261
Keywords
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Funding
- EU [BLUEPRINT-282510]
- Dutch Cancer Foundation [KWF KUN 2009-4527, KUN 2011-4937]
- Netherlands Organization for Scientific Research (NWO-VIDI)
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The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16; 21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16; 21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16; 21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.
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