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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-05-1374.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1141-1148
NEOPLASIA
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, and
Scott C. Kogan
From the Comprehensive Cancer Center and
Department of Laboratory Medicine, University of California, San
Francisco; Harvard Institutes of Medicine, Harvard Medical School,
Boston, MA; Division of Hematology/Oncology, Cedars-Sinai Medical
Center, University of California, Los Angeles School of Medicine;
Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas
Jefferson University, Philadelphia, PA; and Advanced Clinical Research
Center, Institute of Medical Science, University of Tokyo,
Japan.
CCAAT/enhancer binding proteins (C/EBPs) are a family of factors
that regulate cell growth and differentiation. These factors, particularly C/EBP and C/EBP , 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 (PML-RAR) fusion protein is expressed as a result of a
t(15;17)(q22;q12) chromosomal translocation. PML-RAR inhibits expression of C/EBP, whereas all-trans retinoic acid
(tRA), a differentiating agent to which APL is particularly
susceptible, induces C/EBP expression. PML-RAR may also inhibit
C/EBP activity. Thus, the effects of PML-RAR 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/EBP and
C/EBP 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/EBP, we observed
that C/EBP 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.
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