Downregulation of RUNX1/CBFβ by MLL fusion proteins enhances hematopoietic stem cell self-renewal.
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 fusions on 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 acute myeloid 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.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
Xinghui
X
Zhao
Aili
A
Chen
Xiaomei
X
Yan
Yue
Y
Zhang
Fuhong
F
He
Yoshihiro
Y
Hayashi
Yunzhu
Y
Dong
Yalan
Y
Rao
Bo
B
Li
Rajeana M
RM
Conway
Alba
A
Maiques-Diaz
Shannon E
SE
Elf
Nuomin
N
Huang
Johannes
J
Zuber
Zhijian
Z
Xiao
William
W
Tse
Daniel G
DG
Tenen
Qianfei
Q
Wang
Wei
W
Chen
James C
JC
Mulloy
Stephen D
SD
Nimer
Gang
G
Huang
D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic
C493692:CBFB protein, human; C493693:Cbfb protein, mouse; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C474558:MLL-AF9 fusion protein, human; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein