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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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CCAAT-Enhancer-Binding Proteins
Acute Myeloid Leukemia
Phenotype
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Leukemia
Tretinoin
Myelopoiesis

ASJC Scopus subject areas

  • Hematology

Cite this

Truong, B. T. H., Lee, Y. J., Lodie, T. A., Park, D. J., Perrotti, D., Watanabe, N., ... 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

CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. / Truong, Bao Tran H; Lee, Young Jin; Lodie, Tracey A.; Park, Dorothy J.; Perrotti, Danilo; Watanabe, Naohide; Koeffler, H. Phillip; Nakajima, Hideaki; Tenen, Daniel G.; Kogan, Scott C.

In: Blood, Vol. 101, No. 3, 01.02.2003, p. 1141-1148.

Research output: Contribution to journalArticle

Truong, BTH, Lee, YJ, Lodie, TA, Park, DJ, Perrotti, D, Watanabe, N, Koeffler, HP, Nakajima, H, Tenen, DG & Kogan, SC 2003, 'CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia', Blood, vol. 101, no. 3, pp. 1141-1148. https://doi.org/10.1182/blood-2002-05-1374
Truong BTH, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N et al. CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood. 2003 Feb 1;101(3):1141-1148. https://doi.org/10.1182/blood-2002-05-1374
Truong, Bao Tran H ; Lee, Young Jin ; Lodie, Tracey A. ; Park, Dorothy J. ; Perrotti, Danilo ; Watanabe, Naohide ; Koeffler, H. Phillip ; Nakajima, Hideaki ; Tenen, Daniel G. ; Kogan, Scott C. / CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. In: Blood. 2003 ; Vol. 101, No. 3. pp. 1141-1148.
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AU - Perrotti, Danilo

AU - Watanabe, Naohide

AU - Koeffler, H. Phillip

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AU - Kogan, Scott C.

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