title: Bone marrow stroma cells regulate TIEG1 expression in acute lymphoblastic leukemia cells: role of TGFbeta/BMP-6 and TIEG1 in chemotherapy escape.
abstract: The bone marrow microenvironment regulates early B lymphopoiesis and protects leukemia cells against chemotherapy treatment, thus the microenvironment may serve as a sanctuary site for these cells. Yet, few factors that contribute to this process are known. We have explored the role of transforming growth factor beta (TGFbeta) and bone morphogenetic protein-6 (BMP-6) and one target gene, TGFbeta inducible early gene 1 (TIEG1), in the communication between stroma cells and acute lymphoblastic leukemia (ALL) cell lines and their escape from chemotherapy. Here, we have demonstrated TIEG1 expression in both normal B progenitor cells and ALL cells, which increased rapidly upon TGFbeta and BMP-6 treatment. Stimulation with TGFbeta or BMP-6, as well as overexpression of TIEG1 inhibited proliferation. Furthermore, interaction with stroma cells induced TIEG1 expression in ALL cells, inhibited their proliferation and protected the cells against chemotherapeutic treatment. Similarly, treatment with TGFbeta or BMP-6, as well as overexpression of TIEG1, protected ALL cells against chemotherapy-induced cell death. These data suggest that TGFbeta and BMP-6 in the bone marrow microenvironment allow leukemia cells to escape therapy. Further, the data indicate that TIEG1 might be involved in mediating this effect from the microenvironment onto the leukemia cells.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, Oslo, Norway.
authors.forename: Guri
authors.initials: G
authors.lastname: Døsen-Dahl
authors.forename: Else
authors.initials: E
authors.lastname: Munthe
authors.forename: Marit Kveine
authors.initials: MK
authors.lastname: Nygren
authors.forename: Heidi
authors.initials: H
authors.lastname: Stubberud
authors.forename: Marit E
authors.initials: ME
authors.lastname: Hystad
authors.forename: Edith
authors.initials: E
authors.lastname: Rian
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism*; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D051765:Early Growth Response Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D046228:Microarray Analysis; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D051765:Early Growth Response Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D016212:Transforming Growth Factor beta