RhoGTPases and p53 are involved in the morphological appearance and interferon-alpha response of hairy cells

Am J Pathol. 2006 Feb;168(2):562-73. doi: 10.2353/ajpath.2006.050345.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Antineoplastic Agents / pharmacology*
  • Enzyme Induction / drug effects
  • Guanosine Triphosphate / metabolism
  • Humans
  • Interferon-alpha / pharmacology*
  • Leukemia, Hairy Cell* / metabolism
  • Leukemia, Hairy Cell* / pathology
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism*
  • cdc42 GTP-Binding Protein / metabolism*
  • rac1 GTP-Binding Protein / metabolism*
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Actins
  • Antineoplastic Agents
  • Interferon-alpha
  • RAC1 protein, human
  • Tumor Suppressor Protein p53
  • RHOA protein, human
  • Guanosine Triphosphate
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein