Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

ABSTRACT

PLZF is a transcription factor that confers aberrant self-renewal in leukemogenesis, and the PLZF-RARA fusion gene causes acute promyelocytic leukemia (APL) through differentiation block. However, the molecular mechanisms of aberrant self-renewal underlying PLZF-mediated leukemogenesis are poorly understood. To investigate these mechanisms, comprehensive expression profiling of mouse hematopoietic stem/progenitor cells transduced with Plzf was performed, which revealed the involvement of a key transcriptional coactivator, Eya2, a target molecule shared by Plzf and PLZF-RARA, in the aberrant self-renewal. Indeed, PLZF-RARA as well as Plzf rendered those cells immortalized through upregulation of Eya2. Eya2 also led to immortalization without differentiation block, while depletion of Eya2 suppressed clonogenicity in cells immortalized by PLZF-RARA without influence on differentiation and apoptosis. Interestingly, cancer outlier profile analysis of human samples of acute myeloid leukemia (AML) in The Cancer Genome Atlas (TCGA) revealed a subtype of AML that strongly expressed EYA2. In addition, gene set enrichment analysis of human AML samples, including TCGA data, showed that this subtype of AML was more closely associated with the properties of leukemic stem cells in its gene expression signature than other AMLs. Therefore, EYA2 may be a target for molecular therapy in this subtype of AML, including PLZF-RARA APL.

KEYWORD:

• leukemia

ACKNOWLEDGMENTS

We thank Makoto Kimura for a plasmid harboring the blasticidin S deaminase gene, the TCGA Research Network for providing data, and Palabra, Inc. (Kyoto, Japan), for language assistance.

R.O. and T.N. designed the research. R.O., M.M., and S.I. performed experiments. R.O., N.K., and T.N. analyzed the results. R.O. and T.N. wrote the manuscript.

This study was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (T.N.; Basic-B; 26293247), the Foundation for Promotion of Cancer Research (R.O.), Sanikai (R.O.), the Japan Leukemia Research Fund (T.N.), Okasan-Kato Foundation (T.N.), and the Mie University Hospital Seed Grant Program (T.N.).

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

We declare we have no competing financial interests.