Alteration of phosphatidylinositol 3-kinase cascade in the multilobulated nuclear formation of adult T cell leukemia/lymphoma (ATLL).
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.
Fukuda
Ryu-ichi
R
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Hayashi
Ayako
A
Utsunomiya
Atae
A
Nukada
Yuko
Y
Fukui
Rie
R
Itoh
Katsuhiko
K
Tezuka
Katsunari
K
Ohashi
Kazumasa
K
Mizuno
Kensaku
K
Sakamoto
Manabu
M
Hamanoue
Masahiro
M
Tsuji
Takashi
T
D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism / Q000648:ultrastructure; D049109:Cell Proliferation; D004789:Enzyme Activation; D015368:Human T-lymphotropic virus 1; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D000072181:Inositol Polyphosphate 5-Phosphatases; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000473:pathology; D008870:Microtubules / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000821:virology
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases