| First Author | Zhao X | Year | 2014 |
| Journal | Blood | Volume | 123 |
| Issue | 11 | Pages | 1729-38 |
| PubMed ID | 24449215 | Mgi Jnum | J:209654 |
| Mgi Id | MGI:5568281 | Doi | 10.1182/blood-2013-03-489575 |
| Citation | Zhao X, et al. (2014) Downregulation of RUNX1/CBFbeta by MLL fusion proteins enhances hematopoietic stem cell self-renewal. Blood 123(11):1729-38 |
| abstractText | RUNX1/CBFbeta (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/CBFbeta recruits MLL to regulate downstream target genes. However, the functional consequence of MLL fusions on RUNX1/CBFbeta 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 CBFbeta protein expression via the MLL CXXC domain and flanking regions. We confirmed this finding in Mll-Af9 knock-in mice and human M4/M5 acute myeloid leukemia (AML) cell lines, with or without MLL translocations, showing that MLL translocations cause a hypomorph phenotype of RUNX1/CBFbeta. Overexpression of RUNX1 inhibits the development of AML in Mll-Af9 knock-in mice; conversely, further reducing Runx1/Cbfbeta levels accelerates MLL-AF9-mediated AML in bone marrow transplantation assays. These data reveal a newly defined negative regulation of RUNX1/CBFbeta by MLL fusion proteins and suggest that targeting RUNX1/CBFbeta levels may be a potential therapy for MLLs. |
