RRC ID 68563
Author Manshouri T, Estrov Z, Quintás-Cardama A, Burger J, Zhang Y, Livun A, Knez L, Harris D, Creighton CJ, Kantarjian HM, Verstovsek S.
Title Bone marrow stroma-secreted cytokines protect JAK2(V617F)-mutated cells from the effects of a JAK2 inhibitor.
Journal Cancer Res
Abstract Signals emanating from the bone marrow microenvironment, such as stromal cells, are thought to support the survival and proliferation of the malignant cells in patients with myeloproliferative neoplasms (MPN). To examine this hypothesis, we established a coculture platform [cells cocultured directly (cell-on-cell) or indirectly (separated by micropore membrane)] designed to interrogate the interplay between Janus activated kinase 2-V617F (JAK2(V617F))-positive cells and the stromal cells. Treatment with atiprimod, a potent JAK2 inhibitor, caused marked growth inhibition and apoptosis of human (SET-2) and mouse (FDCP-EpoR) JAK2(V617F)-positive cells as well as primary blood or bone marrow mononuclear cells from patients with polycythemia vera; however, these effects were attenuated when any of these cell types were cocultured (cell-on-cell) with human marrow stromal cell lines (e.g., HS5, NK.tert, TM-R1). Coculture with stromal cells hampered the ability of atiprimod to inhibit phosphorylation of JAK2 and the downstream STAT3 and STAT5 pathways. This protective effect was maintained in noncontact coculture assays (JAK2(V617F)-positive cells separated by 0.4-μm-thick micropore membranes from stromal cells), indicating a paracrine effect. Cytokine profiling of supernatants from noncontact coculture assays detected distinctly high levels of interleukin 6 (IL-6), fibroblast growth factor (FGF), and chemokine C-X-C-motif ligand 10 (CXCL-10)/IFN-γ-inducible 10-kD protein (IP-10). Anti-IL-6, -FGF, or -CXCL-10/IP-10 neutralizing antibodies ablated the protective effect of stromal cells and restored atiprimod-induced apoptosis of JAK2(V617F)-positive cells. Therefore, our results indicate that humoral factors secreted by stromal cells protect MPN clones from JAK2 inhibitor therapy, thus underscoring the importance of targeting the marrow niche in MPN for therapeutic purposes.
Volume 71(11)
Pages 3831-40
Published 2011-6-1
DOI 10.1158/0008-5472.CAN-10-4002
PII 0008-5472.CAN-10-4002
PMID 21512135
PMC PMC4067142
MeSH Animals Apoptosis / drug effects Apoptosis / immunology Bone Marrow Cells / enzymology Bone Marrow Cells / immunology Bone Marrow Cells / physiology* Cell Growth Processes / drug effects Cell Growth Processes / immunology Cell Line, Tumor Cytokines / genetics Cytokines / immunology* Drug Resistance Humans Interleukin-6 / genetics Interleukin-6 / immunology Janus Kinase 2 / antagonists & inhibitors* Janus Kinase 2 / genetics Janus Kinase 2 / metabolism Mice Mutation Myeloproliferative Disorders / drug therapy* Myeloproliferative Disorders / genetics Myeloproliferative Disorders / immunology* Myeloproliferative Disorders / pathology Signal Transduction Spiro Compounds / pharmacology Stromal Cells / drug effects Stromal Cells / immunology Transfection
IF 9.727
Human and Animal Cells StromaNKtert(RCB2350)