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An evolutionarily conserved PTEN-C/EBP-CTNNA1 axis controls myeloid development and transformation
Chun-Tang Fu1, Kang-Yong Zhu1, Jian-Qing Mi1, Yuan-Fang Liu1, Susan T. Murray2, Yan-Fang Fu1, Chun-Guang Ren1, Zhi-Wei Dong1, Yi-Jie Liu1, Mei Dong1, Yi Jin1, Yi Chen1, Min Deng1, Wu Zhang1, Bin Chen1, Peter Breslin3, Sai-Juan Chen1, Zhu Chen1, Michael W. Becker2, Jiang Zhu1, Ji-Wang Zhang3 and Ting Xi Liu4,*
1 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China; 2 Division of Hematology/Oncology, University of Rochester, Rochester, NY, United States; 3 Pathology Department, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, United States; 4 Shanghai Stem Cell Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Loss of function of tumor suppressor genes such as PTEN, C/EBPA and CTNNA1 has been found to play essential roles in leukemogenesis. However, whether these genes genetically interact remains unknown. We previously reported that the CTNNA1 gene is expressed at a very low level in the HL-60 cell line and in primary leukemia-initiating cells (LICs) with a 5q deletion. Here, we show that PTEN-mTOR signaling acts upstream to dictate the ratio of wild-type p42 C/EBP to its dominant-negative p30 isoform, which critically determines whether p30 C/EBP (lower p42/p30 ratio) or p42 C/EBP (higher p42/p30 ratio) binds to the proximal promoter of the retained CTNNA1 allele. Binding of p30 C/EBP recruits the PRC2 complex to suppress CTNNA1 transcription through repressive H3K27me3 modification, whereas binding of p42 C/EBP 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/EBP and -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/EBP-CTNNA1, which might be therapeutically targeted to eradicate LICs with low CTNNA1 expression.
