CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia

Bao Tran H. Truong, Young Jin Lee, Tracey A. Lodie, Dorothy J. Park, Danilo Perrotti, Naohide Watanabe, H. Phillip Koeffler, Hideaki Nakajima, Daniel G. Tenen, Scott C. Kogan

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90 Citations (Scopus)

Abstract

CCAAT/enhancer binding proteins (C/EBPs) are a family of factors that regulate cell growth and differentiation. These factors, particularly C/EBPα and C/EBPε, have important roles in normal myelopoiesis. In addition, loss of C/EBP activity appears to have a role in the pathogenesis of myeloid disorders including acute myeloid leukemia (AML). Acute promyelocytic leukemia (APL) is a subtype of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion protein is expressed as a result of a t(15;17)(q22; q12) chromosomal translocation. PML-RARα inhibits expression of C/EBPε, whereas all-trans retinoic acid (tRA), a differentiating agent to which APL is particularly susceptible, induces C/EBPε expression. PML-RARα may also inhibit C/EBPα activity. Thus, the effects of PML-RARα on C/EBPs may contribute to both the development of leukemia and the unique sensitivity of APL to tRA. We tested the hypothesis that increasing the activity of C/EBPs would revert the leukemic phenotype. C/EBPα and C/EBPε were introduced into the FDC-P1 myeloid cell line and into leukemic cells from PML-RARA transgenic mice. C/EBP factors suppressed growth and induced partial differentiation in vitro. In vivo, enhanced expression of C/EBPs prolonged survival. By using a tamoxifen-responsive version of C/EBPε, we observed that C/EBPε could mimic the effect of tRA, driving neutrophilic differentiation in leukemic animals. Our results support the hypothesis that induction of C/EBP activity is a critical effect of tRA in APL. Furthermore, our findings suggest that targeted modulation of C/EBP activities could provide a new approach to therapy of AML.

Original languageEnglish
Pages (from-to)1141-1148
Number of pages8
JournalBlood
Volume101
Issue number3
DOIs
Publication statusPublished - 2003 Feb 1

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Truong, B. T. H., Lee, Y. J., Lodie, T. A., Park, D. J., Perrotti, D., Watanabe, N., Koeffler, H. P., Nakajima, H., Tenen, D. G., & Kogan, S. C. (2003). CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood, 101(3), 1141-1148. https://doi.org/10.1182/blood-2002-05-1374