CD11c gene expression in hairy cell leukemia is dependent upon activation of the proto-oncogenes ras and junD.
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 beta2 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.
Nicolaou
Fotini
F
Renal Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Teodoridis
Jens M
JM
Park
Heiyoung
H
Georgakis
Alexander
A
Farokhzad
Omid C
OC
Böttinger
Erwin P
EP
Da Silva
Nicolas
N
Rousselot
Philippe
P
Chomienne
Christine
C
Ferenczi
Katalin
K
Arnaout
M Amin
MA
Shelley
C Simon
CS
D015703:Antigens, CD / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D002070:Butadienes / Q000494:pharmacology; D039521:CD11c Antigen / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016758:Genes, jun; D011905:Genes, ras; D006367:HeLa Cells; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D009570:Nitriles / Q000494:pharmacology; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D015703:Antigens, CD; D002070:Butadienes; D039521:CD11c Antigen; D004791:Enzyme Inhibitors; D009570:Nitriles; D018808:Transcription Factor AP-1; C113580:U 0126