title: Reciprocal leukemia-stroma VCAM-1/VLA-4-dependent activation of NF-κB mediates chemoresistance.
abstract: Leukemia cells are protected from chemotherapy-induced apoptosis by their interactions with bone marrow mesenchymal stromal cells (BM-MSCs). Yet the underlying mechanisms associated with this protective effect remain unclear. Genome-wide gene expression profiling of BM-MSCs revealed that coculture with leukemia cells upregulated the transcription of genes associated with nuclear factor (NF)-κB signaling. Moreover, primary BM-MSCs from leukemia patients expressed NF-κB target genes at higher levels than their normal BM-MSC counterparts. The blockade of NF-κB activation via chemical agents or the overexpression of the mutant form of inhibitor κB-α (IκBα) in BM-MSCs markedly reduced the stromal-mediated drug resistance in leukemia cells in vitro and in vivo. In particular, our unique in vivo model of human leukemia BM microenvironment illustrated a direct link between NF-κB activation and stromal-associated chemoprotection. Mechanistic in vitro studies revealed that the interaction between vascular cell adhesion molecule 1 (VCAM-1) and very late antigen-4 (VLA-4) played an integral role in the activation of NF-κB in the stromal and tumor cell compartments. Together, these results suggest that reciprocal NF-κB activation in BM-MSCs and leukemia cells is essential for promoting chemoresistance in the transformed cells, and targeting NF-κB or VLA-4/VCAM-1 signaling could be a clinically relevant mechanism to overcome stroma-mediated chemoresistance in BM-resident leukemia cells.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Jacamo
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Erika L
authors.initials: EL
authors.lastname: Spaeth
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Venkata L
authors.initials: VL
authors.lastname: Battula
authors.forename: Po Yee
authors.initials: PY
authors.lastname: Mak
authors.forename: Katharina
authors.initials: K
authors.lastname: Schallmoser
authors.forename: Peter
authors.initials: P
authors.lastname: Ruvolo
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Schober
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Martin H
authors.initials: MH
authors.lastname: Nguyen
authors.forename: Dirk
authors.initials: D
authors.lastname: Strunk
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Bueso-Ramos
authors.forename: Sergej
authors.initials: S
authors.lastname: Konoplev
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000166:cytology; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D039041:Integrin alpha4beta1; D016328:NF-kappa B; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1