Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL)

Ryu Ichi Fukuda, Ayako Hayashi, Atae Utsunomiya, Yuko Nukada, Rie Fukui, Katsuhiko Itoh, Katsunari Tezuka, Kazumasa Ohashi, Kensaku Mizuno, Manabu Sakamoto, Masahiro Hamanoue, Takashi Tsuji

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

Abstract

Adult T cell leukemia/lymphoma (ATLL) has been characterized as one of the most aggressive human neoplasias and its incidence is thought to be caused by both genetic and epigenetic alterations to the host cellular genes of T cells infected with human T cell leukemia virus type I (HTLV-I). A multilobulated nuclear appearance is an important diagnostic marker of ATLL, and we have now identified that the molecular mechanisms underlying these formations occur through microtubule rearrangement via phosphatidylinositol 3-kinase (PI3-kinase) activation by AILIM/ICOS signaling. We also show that PTEN and/or SHIP-1, which are PIP3 inositol phosphatases that inhibit the activation of downstream effectors of the PI3-kinase cascade, are disrupted in both ATLL neoplasias and in multilobulated nuclei-forming Jurkat cells. This down-regulation of PTEN was found to be essential for the formation of ATLL-type nuclear lobules. Furthermore, PI3-kinase and PTEN activities were observed to be closely associated with cellular proliferation. Thus, our results suggest that alteration of PI3-kinase signaling cascades, as a result of the down-regulation of inositol phosphatases, induces ATLL-type multilobulated nuclear formation and is also associated with the cellular proliferation of malignant T cell leukemias lymphomas.

Original languageEnglish
Pages (from-to)15213-15218
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number42
DOIs
Publication statusPublished - 2005 Oct 18

Keywords

  • Activation-inducible lymphocyte immunomediatory molecule/inducible costimulator
  • Human T cell leukemia virus type I
  • Multilobulated nuclei
  • PTEN
  • SHIP

ASJC Scopus subject areas

  • General

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