Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis.
The RUNX1/AML1 gene is the most frequently mutated gene in human leukemia. Conditional deletion of Runx1 in adult mice results in an increase of hematopoietic stem cells (HSCs), which serve as target cells for leukemia; however, Runx1(-/-) mice do not develop spontaneous leukemia. Here we show that maintenance of Runx1(-/-) HSCs is compromised, progressively resulting in HSC exhaustion. In leukemia development, the stem cell exhaustion was rescued by additional genetic changes. Retroviral insertional mutagenesis revealed Evi5 activation as a cooperating genetic alteration and EVI5 overexpression indeed prevented Runx1(-/-) HSC exhaustion in mice. Moreover, EVI5 was frequently overexpressed in human RUNX1-related leukemias. These results provide insights into the mechanism for maintenance of pre-leukemic stem cells and may provide a novel direction for therapeutic applications.
Jacob
Bindya
B
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore.
Osato
Motomi
M
Yamashita
Namiko
N
Wang
Chelsia Qiuxia
CQ
Taniuchi
Ichiro
I
Littman
Dan R
DR
Asou
Norio
N
Ito
Yoshiaki
Y
D000818:Animals; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit; D020690:GTPase-Activating Proteins; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D014157:Transcription Factors
D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; C506399:EVI5 protein, human; C105043:Evi5 protein, mouse; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D014157:Transcription Factors