Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal Journal Article
| Authors: | Zhao, X.; Chen, A.; Yan, X.; Zhang, Y.; He, F.; Hayashi, Y.; Dong, Y.; Rao, Y.; Li, B.; Conway, R. M.; Maiques-Diaz, A.; Elf, S. E.; Huang, N.; Zuber, J.; Xiao, Z.; Tse, W.; Tenen, D. G.; Wang, Q.; Chen, W.; Mulloy, J. C.; Nimer, S. D.; Huang, G. |
| Article Title: | Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal |
| Abstract: | RUNX1/CBFβ (core binding factor [CBF]) is a heterodimeric transcription factor complex that is frequently involved in chromosomal translocations, point mutations, or deletions in acute leukemia. The mixed lineage leukemia (MLL) gene is also frequently involved in chromosomal translocations or partial tandem duplication in acute leukemia. The MLL protein interacts with RUNX1 and prevents RUNX1 from ubiquitin-mediated degradation. RUNX1/CBFβ recruits MLL to regulate downstream target genes. However, the functional consequence of MLL fusionson RUNX1/CBFβ activity has not been fully understood. In this report, we show that MLL fusion proteins and the N-terminal MLL portion of MLL fusions downregulate RUNX1 and CBFβ protein expression via the MLL CXXC domain and flanking regions. We confirmed this finding in Mll-Af9 knock-in mice and human M4/M5 acutemyeloid leukemia (AML) cell lines, with or without MLL translocations, showing that MLL translocations cause a hypomorph phenotype of RUNX1/CBFβ. Overexpression of RUNX1 inhibits the development of AML in Mll-Af9 knock-in mice; conversely, further reducing Runx1/Cbfβ levels accelerates MLL-AF9-mediated AML in bone marrow transplantation assays. These data reveal a newly defined negative regulation of RUNX1/CBFβ by MLL fusion proteins and suggest that targeting RUNX1/CBFβ levels may be a potential therapy for MLLs. © 2014 by The American Society of Hematology. |
| Keywords: | controlled study; protein expression; acute granulocytic leukemia; gene translocation; human cell; nonhuman; protein domain; protein function; mouse; phenotype; gene overexpression; animal experiment; animal model; cell renewal; amino terminal sequence; leukemia cell; dna flanking region; hematopoietic stem cell; bone marrow transplantation; leukemia cell line; transcription factor runx1; mediator; receptor down regulation; mixed lineage leukemia protein; human; priority journal; article; core binding factor beta |
| Journal Title: | Blood |
| Volume: | 123 |
| Issue: | 11 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2014-03-13 |
| Start Page: | 1729 |
| End Page: | 1738 |
| Language: | English |
| DOI: | 10.1182/blood-2013-03-489575 |
| PROVIDER: | scopus |
| PUBMED: | 24449215 |
| PMCID: | PMC4067497 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: BLOOA -- Source: Scopus |
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