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Prepublished online as a Blood First Edition Paper on October 3, 2002; DOI 10.1182/blood-2002-05-1374.
Submitted May 10, 2002
Accepted September 14, 2002
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*
Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
Harvard Medical School, Boston, MA, USA
Division of Hematology/Oncology, UCLA School of Medicine-Cedars-Sinai Medical Center, Los Angeles, CA, USA
Department of Microbiology and Immunology, Kimmel Cancer Ctr-Thomas Jefferson University, Philadelphia, PA, USA
Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
* Corresponding author; email: skogan{at}cc.ucsf.edu.
CCAAT/enhancer binding proteins 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. Acute promyelocytic leukemia is a sub-type of AML in which a role for C/EBPs has been postulated. In almost all cases of APL, a 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, effects of PML-RAR on C/EBPs may contribute to both the development of leukemia and to 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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