Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult.
The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In human RUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/progenitor cell fraction because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemia-initiating cells expressing an activated oncogene. Disclosure of potential conflicts of interest is found at the end of this article.
Motoda
Lena
L
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore.
Osato
Motomi
M
Yamashita
Namiko
N
Jacob
Bindya
B
Chen
Lynnette Q
LQ
Yanagida
Masatoshi
M
Ida
Hiroshi
H
Wee
Hee-Jun
HJ
Sun
Alfred X
AX
Taniuchi
Ichiro
I
Littman
Dan
D
Ito
Yoshiaki
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism