title: Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia.
abstract: Evidence suggests that tumor microenvironment is critically involved in supporting survival of chronic lymphocytic leukemia (CLL) cells. However, the molecular mechanisms of this effect and the clinical significance are not fully understood. We applied a microenvironment model to explore the interaction between CLL cells and stromal cells and to elucidate the role of phosphatidylinositol 3 kinase (PI3-K)/Akt/phosphatase and tensin homolog detected on chromosome 10 (PTEN) cascade in this process and its in vivo relevance. Primary human stromal cells from bone marrow, lymph nodes, and spleen significantly inhibited spontaneous apoptosis of CLL cells. Pan-PI3-K inhibitors (LY294002, wortmannin, PI-103), isotype-specific inhibitors of p110α, p110β, p110γ, and small interfering RNA against PI3-K and Akt1 counteracted the antiapoptotic effect of the stromal cells. Induction of apoptosis was associated with a decrease in phosphatidylinositol-3,4,5-triphosphate, PI3-K-p85, and dephosphorylation of phosphatidylinositol-dependent kinase-1 (PDK-1), Akt1, and PTEN. Freshly isolated peripheral blood mononuclear cells from patients with CLL (n = 44) showed significantly higher levels of phosphorylated Akt1, PDK-1, PTEN, and CK2 than healthy persons (n = 8). CK2 inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole, apigenin, and 5,6-dichloro-1-β-D-ribofuranosylbenzimidazol) decreased phosphorylation of PTEN and Akt, induced apoptosis in CLL cells, and enhanced the response to fludarabine. In conclusion, bone marrow microenvironment modulates the PI3-K/Akt/PTEN cascade and prevents apoptosis of CLL cells. Combined inhibition of PI3-K/Akt and recovery of PTEN activity may represent a novel therapeutic concept for CLL.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria. medhat.shehata@meduniwien.ac.at
authors.forename: Medhat
authors.initials: M
authors.lastname: Shehata
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnabl
authors.forename: Dita
authors.initials: D
authors.lastname: Demirtas
authors.forename: Martin
authors.initials: M
authors.lastname: Hilgarth
authors.forename: Rainer
authors.initials: R
authors.lastname: Hubmann
authors.forename: Elena
authors.initials: E
authors.lastname: Ponath
authors.forename: Sigrun
authors.initials: S
authors.lastname: Badrnya
authors.forename: Claudia
authors.initials: C
authors.lastname: Lehner
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoelbl
authors.forename: Markus
authors.initials: M
authors.lastname: Duechler
authors.forename: Alexander
authors.initials: A
authors.lastname: Gaiger
authors.forename: Christoph
authors.initials: C
authors.lastname: Zielinski
authors.forename: Josef D
authors.initials: JD
authors.lastname: Schwarzmeier
authors.forename: Ulrich
authors.initials: U
authors.lastname: Jaeger
mesh_terms: D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D047390:Casein Kinase II / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D058539:Phosphatidylinositol 3-Kinase; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human