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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-01-0324.
Submitted January 31, 2002
Accepted December 5, 2002
CD11c gene expression in hairy-cell leukemia is dependent upon activation of the proto-oncogenes Ras and JunD
Fotini Nicolaou, Jens M Teodoridis, Heiyoung Park, Alexander Georgakis, Omid C Farokhzad, Erwin P Boettinger, Nicolas Da Silva, Philippe Rousselot, Christine Chomienne, Katalin Ferenczi, M Amin Arnaout, and Carl Simon Shelley*
Renal Unit, Massachusetts General Hospital, Charlestown, MA, USA
Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
Division of Nephrology, Albert Einstein College of Medicine, Bronx, NY, USA
Institut de Hematologie, Hopital Saint-Louis, Paris, France
Department of Dermatology, Brigham and Women's Hospital, Boston, MA, USA
* Corresponding author; email: shelley{at}receptor.mgh.harvard.edu.
Hairy-cell leukemia (HCL) is a chronic lymphoproliferative disease the cause of which is unknown. Diagnostic of HCL is abnormal expression of the gene which encodes the  2 integrin CD11c. In order to determine the cause of CD11c gene expression in HCL the CD11c gene promoter was characterized. Transfection of the CD11c promoter linked to a luciferase reporter gene indicated that it is sufficient to direct expression in hairy-cells. Mutation analysis demonstrated that of predominant importance to the activity of the CD11c promoter is its interaction with the AP-1 family of transcription factors. Comparison of nuclear extracts prepared from hairy-cells with those prepared from other cell-types indicated that hairy-cells exhibit abnormal constitutive expression of an AP-1 complex containing JunD. Functional inhibition of AP-1 expressed by hairy-cells reduced CD11c promoter activity by 80%. Inhibition of Ras, which represents an upstream activator of AP-1, also significantly inhibited the CD11c promoter. Furthermore, in the hairy-cell line EH, inhibition of Ras signaling through MEK1/2 not only reduced CD11c promoter activity but also reduced both CD11c surface expression and proliferation. Expression in non-hairy-cells of a dominant positive Ras mutant activated the CD11c promoter to levels equivalent to those in hairy-cells. Together, these data indicate that the abnormal expression of the CD11c gene characteristic of HCL is dependent upon activation of the proto-oncogenes Ras and JunD.
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