RhoGTPases and p53 are involved in the morphological appearance and interferon-alpha response of hairy cells.
Hairy cell leukemia is an uncommon B-cell lymphoproliferative disease of unknown etiology in which tumor cells display characteristic microfilamentous membrane projections. Another striking feature of the disease is its exquisite sensitivity to interferon (IFN)-alpha. So far, none of the known IFN-alpha regulatory properties have explained IFN-alpha responsiveness nor have they taken into account the morphological characteristics of hairy cells. IFN-alpha profoundly alters cytoskeletal organization of hairy cells and causes reversion of the hairy appearance into a rounded morphology. Because cytoskeletal rearrangements are controlled by the Rho family of GTPases, we investigated the GTPase activation status in hairy cells and their regulation by IFN-alpha. Using immunolocalization techniques and biochemical assays, we demonstrate that hairy cells display high levels of active Cdc42 and Rac1 and that IFN-alpha down-regulates these activities. In sharp contrast, RhoA activity was low in hairy cells but was increased by IFN-alpha treatment. Finally, IFN-alpha-mediated morphological changes also implicated a p53-induced response. These observations shed light on the mechanism of action of IFN-alpha in hairy cell leukemia and are of potential relevance for the therapeutical applications of this cytokine.
Chaigne-Delalande
Benjamin
B
Unité INSERM 441, Institut National de la Recherché Médicale, France.
Deuve
Lynda
L
Reuzeau
Edith
E
Basoni
Caroline
C
Lafarge
David
D
Varon
Christine
C
Tatin
Florence
F
Anies
Guerric
G
Garand
Richard
R
Kramer
Ijsbrand
I
Génot
Elisabeth
E
D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007943:Leukemia, Hairy Cell / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D000199:Actins; D000970:Antineoplastic Agents; D016898:Interferon-alpha; C107953:RAC1 protein, human; D016159:Tumor Suppressor Protein p53; C066737:RHOA protein, human; D006160:Guanosine Triphosphate; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein