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Prepublished online as a Blood First Edition Paper on February 6, 2003; DOI 10.1182/blood-2002-01-0324.
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Blood, 15 May 2003, Vol. 101, No. 10, pp. 4033-4041
NEOPLASIA
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. Böttinger,
Nicolas Da
Silva,
Philippe Rousselot,
Christine Chomienne,
Katalin Ferenczi,
M. Amin Arnaout, and
C. Simon Shelley
From the Renal Unit, Massachusetts General
Hospital, Charlestown, MA; the Department of Surgery, Beth Israel
Deaconess Medical Center, Boston, MA; the Division of Nephrology,
Albert Einstein College of Medicine, Bronx, NY; Institut de
Hematologié, Hôpital Saint-Louis, Paris, France; and the
Department of Dermatology, Brigham and Women's Hospital, Boston,
MA.
Hairy cell leukemia (HCL) is a chronic lymphoproliferative
disease, the cause of which is unknown. Diagnostic of HCL is abnormal expression of the gene that 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 activator protein-1 (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 mitogen-activated protein
kinase/extracellular signal-regulated kinase kinases 1 and 2 (MEK1/2)
reduced not only CD11c promoter activity but also reduced
both CD11c surface expression and proliferation. Expression in nonhairy
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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