EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells

Abstract

ZNF384-related fusion genes are associated with a distinct subgroup of B-cell precursor acute lymphoblastic leukemias in childhood, with a frequency of approximately 3–4%. We previously identified a novel EP300-ZNF384 fusion gene. Patients with the ZNF384-related fusion gene exhibit a hematopoietic stem cell (HSC) gene expression signature and characteristic immunophenotype with negative or low expression of CD10 and aberrant expression of myeloid antigens, such as CD33 and CD13. However, the molecular basis of this pathogenesis remains completely unknown. In the present study, we examined the biological effects of EP300-ZNF384 expression induced by retrovirus-mediated gene transduction in an REH B-cell precursor acute lymphoblastic leukemia cell line, and observed the acquisition of the HSC gene expression signature and an up-regulation of GATA3 gene expression, as assessed by microarray analysis. In contrast, the gene expression profile induced by wild-type ZNF384 in REH cells was significantly different from that by EP300-ZNF384 expression. Together with the results of reporter assays, which revealed the enhancement of GATA3-promoter activity by EP300-ZNF384 expression, these findings suggest that EP300-ZNF384 mediates GATA3 gene expression and may be involved in the acquisition of the HSC gene expression signature and characteristic immunophenotype in B-cell precursor acute lymphoblastic leukemia cells.

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Acknowledgements

We thank Y. Katayama, K. Nakasato, and S. Tamura for their excellent assistance. This work was supported in part by a Health and Labour Sciences Research Grant (3rd-term comprehensive 10-year strategy for cancer control H22-011) and a Grant of the National Center for Child Health and Development (26-20) from the Ministry of Health, Labour and Welfare of Japan, Advanced research for medical products Mining Programme of the National Institute of Biomedical Innovation (NIBIO, 10-41, -42, -43, -44, -45), Tailor-made Medical Treatment Program (BioBank Japan: BBJ), and the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and development, AMED.

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Correspondence to Nobutaka Kiyokawa.

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Yaguchi, A., Ishibashi, T., Terada, K. et al. EP300-ZNF384 fusion gene product up-regulates GATA3 gene expression and induces hematopoietic stem cell gene expression signature in B-cell precursor acute lymphoblastic leukemia cells. Int J Hematol 106, 269–281 (2017). https://doi.org/10.1007/s12185-017-2220-6

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Keywords

  • EP300
  • ZNF384
  • GATA3
  • CD33
  • Transcription