Originally published as JCO Early Release 10.1200/JCO.2008.17.9812 on December 15 2008

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Dysregulation of the C/EBP Differentiation Pathway in Human Cancer

Steffen Koschmieder, Balazs Halmos, Elena Levantini, Daniel G. Tenen

From the University of Münster, Münster, Germany; Case Western Reserve University, Cleveland, OH; Cancer Science Institute of Singapore, Singapore; and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.

Corresponding author: Daniel G. Tenen, Center for Life Sciences, Room 437, 3 Blackfan Circle, Boston, MA 02115; e-mail: dtenen{at}bidmc.harvard.edu.

While much is known about aberrant pathways affecting cell growth and apoptosis, our understanding of another critical step of neoplastic transformation, differentiation arrest, remains poor. The differentiation-inducing transcription factor CCAAT enhancer binding protein alpha (C/EBP) is required for proper control of adipogenesis, glucose metabolism, granulocytic differentiation, and lung development. Studies investigating the function of this protein in hematopoietic malignancies as well as in lung and skin cancer have revealed numerous ways how tumor cells abrogate C/EBP function. Genetic and global expression analysis of acute myeloid leukemia (AML) cases identifies C/EBP-deficient AML as a separate entity yielding novel classification schemes. In patients with a dysfunctional C/EBP pathway, targeted therapies may overcome the block in differentiation, and in combination with conventional chemotherapy, may lead to complete eradication of the malignant clone. Overall, a better understanding of the mechanisms of how C/EBP dysregulation participates in the neoplastic process has opened new gateways for differentiation biology research.

*S.K. and B.H. have contributed equally to this manuscript.

Supported by National Institutes of Health/National Cancer Institute's "SPORE in Human Lung Cancer" P50 CA90578-04 (B.H. and D.G.T.) and RO1 CA118316 (D.G.T.), the Flight Attendant Medical Research Institute (B.H. and E.L.), the International Association for the Study of Lung Cancer (E.L.), and a grant of the Deutsche Forschungsgemeinschaft (DFG KO2155/1-1 and /2-1; S.K.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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