title: Bone marrow stromal cells protect acute myeloid leukemia cells from anti-CD44 therapy partly through regulating PI3K/Akt-p27(Kip1) axis.
abstract: The anti-CD44 monoclonal antibody (mAb) A3D8 induces differentiation or apoptosis in vitro in various subtypes of acute myeloid leukemia (AML) via p27(Kip1) upregulation. Bone marrow (BM) stromal cells play a vital role in the development of chemoresistance in AML cells attached to the stroma. To investigate the effect of BM stroma adhesion induced AML resistance to A3D8, we developed a co-culture system composed of an AML-derived cell line (NB4) cultured with either a human BM stroma cell line (HS-5) or mesenchymal stem cells (MSCs). We found that NB4 cells adhered to HS-5 cells or MSCs developed resistance against the anti-proliferative effects of A3D8, and this action is caused by the activation of PI3K/Akt signaling following p27(Kip1) down-regulation and cytoplasmic re-localization. The stromal co-culture-induced resistance can be partially abolished by inhibiting the PI3K/Akt signaling pathway. Such findings were confirmed in two additional AML-derived cell lines as well as in primary AML cells. Our results suggest that BM stroma can induce A3D8 resistance in part via the PI3K/Akt-p27(Kip1) axis, and blocking PI3K/Akt pathway maybe necessary for anti-CD44 treatment on AML in BM microenvironment.
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Juanying
authors.initials: J
authors.lastname: Wu
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fuzhou, P.R. China.
authors.forename: Yuanzhong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000276:immunology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; C497483:CD44 protein, human; C436291:CDKN1B protein, human; D018960:Hyaluronan Receptors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: A3D8; PI3K/Akt; acute myeloid leukemia; bone marrow stroma; p27Kip1