Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1.
Dominant RUNX1 inhibition has been proposed as a common pathway for CBF leukemia. CBF beta-SMMHC, a fusion protein in human acute myeloid leukemia (AML), dominantly inhibits RUNX1 largely through its RUNX1 high-affinity binding domain (HABD). However, the type I CBF beta-SMMHC fusion in AML patients lacks HABD. Here, we report that the type I CBF beta-SMMHC protein binds RUNX1 inefficiently. Knockin mice expressing CBF beta-SMMHC with a HABD deletion developed leukemia quickly, even though hematopoietic defects associated with Runx1-inhibition were partially rescued. A larger pool of leukemia-initiating cells, increased MN1 expression, and retention of RUNX1 phosphorylation are potential mechanisms for accelerated leukemia development in these mice. Our data suggest that RUNX1 dominant inhibition may not be a critical step for leukemogenesis by CBF beta-SMMHC.
Kamikubo
Yasuhiko
Y
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Zhao
Ling
L
Wunderlich
Mark
M
Corpora
Takeshi
T
Hyde
R Katherine
RK
Paul
Thomas A
TA
Kundu
Mondira
M
Garrett
Lisa
L
Compton
Sheila
S
Huang
Gang
G
Wolff
Linda
L
Ito
Yoshiaki
Y
Bushweller
John
J
Mulloy
James C
JC
Liu
P Paul
PP
D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007942:Leukemia, Experimental / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding
D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D015514:Oncogene Proteins, Fusion