An evolutionarily conserved PTEN-C/EBPα-CTNNA1 axis controls myeloid development and transformation

Loss of function of tumor suppressor genes, such as PTEN, CEBPΑ, and CTNNA1 (encoding the α-catenin protein), has been found to play an essential role in leukemogenesis. However, whether these genes genetically interact remains largely unknown. Here, we show that PTEN-mammalian target of rapamycin s...

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Published in:Blood 2010-06, Vol.115 (23), p.4715-4724
Main Authors: Fu, Chun-Tang, Zhu, Kang-Yong, Mi, Jian-Qing, Liu, Yuan-Fang, Murray, Susan T., Fu, Yan-Fang, Ren, Chun-Guang, Dong, Zhi-Wei, Liu, Yi-Jie, Dong, Mei, Jin, Yi, Chen, Yi, Deng, Min, Zhang, Wu, Chen, Bin, Breslin, Peter, Chen, Sai-Juan, Chen, Zhu, Becker, Michael W., Zhu, Jiang, Zhang, Ji-Wang, Liu, Ting Xi
Format: Article
Language:English
Subjects:
Biological and medical sciences
Hematologic and hematopoietic diseases
Hematopoiesis and Stem Cells
Medical sciences
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Summary:Loss of function of tumor suppressor genes, such as PTEN, CEBPΑ, and CTNNA1 (encoding the α-catenin protein), has been found to play an essential role in leukemogenesis. However, whether these genes genetically interact remains largely unknown. Here, we show that PTEN-mammalian target of rapamycin signaling acts upstream to dictate the ratio of wild-type p42 C/EBPα to its dominant-negative p30 isoform, which critically determines whether p30 C/EBPα (lower p42/p30 ratio) or p42 C/EBPα (higher p42/p30 ratio) binds to the proximal promoter of the retained CTNNA1 allele. Binding of p30 C/EBPα recruits the polycomb repressive complex 2 to suppress CTNNA1 transcription through repressive H3K27me3 modification, whereas binding of p42 C/EBPα relieves this repression and promotes CTNNA1 expression through activating H3K4me3 modification. Loss of Pten function in mice and zebrafish induces myelodysplasia with abnormal invasiveness of myeloid progenitors accompanied by significant reductions in both wild-type C/EBPα and α-catenin protein. Importantly, frame-shift mutations in either PTEN or CEBPA were detected exclusively in the primary LICs with low CTNNA1 expression. This study uncovers a novel molecular pathway, PTEN-C/EBPα-CTNNA1, which is evolutionarily conserved and might be therapeutically targeted to eradicate LICs with low CTNNA1 expression.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2009-11-255778