Bone marrow stroma-mediated paracrine inhibition of JAK2 inhibitor-induced apoptosis of JAK2V617F- mutated cells (CROSBI ID 574755)
Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | međunarodna recenzija
Podaci o odgovornosti
Manshouri, Taghi ; Quintás-Cardama, Alfonso ; Estrov, Zeev ; Burger, Jan ; Livun, Ana ; Zhang, Ying ; Knez, Liza ; Harris, David ; Creighton, Chad ; Kantarjian, Hagop M. ; Verstovšek Srđan
engleski
Bone marrow stroma-mediated paracrine inhibition of JAK2 inhibitor-induced apoptosis of JAK2V617F- mutated cells
Signals emanating from the bone marrow microenviroment are thought to support the survival and proliferation of the malignant cells in patients with myeloproliferative neoplasms (MPN), and to protect them from therapeutic interventions. Little is known about the crosstalk between MPN clones and the marrow stroma. We have streamlined a co-culture platform designed to interrogate between JAK2V617F-positive cells and the stroma microenviroment. Treatment with atiprimod, a potent JAK2 inhibitor, causes marked apoptosis of both human (SET2) and mouse (FDCP- EpoR)JAK2V617F-positive cells but this effect was attenuated when the latter were co-cultured (cell- on-cell) with human marrow stromal cell lines (HS5, NK tert., or TM-R1). Co-culture with stromal cells hampered the ability of atipromod to inhibit the phosphorylation of JAK2 and the down stream signal transducer and activators of transcription (STAT) 3, and STAT5. Notably, this protective effect was maintained in non-contact co-culture assays (cell lines separated by 0.4 μm micropore membranes), suggesting a paracrine effect. Cytokine profiling of supernatans from the latter culture system detected high levels of IL-6, FGF and CXCL10/IP10, and anti-IL-6, -FGF, or CXCL10/IP10 neutralizing antibodies ablated the protective effect of stromal cells and markedly increased atiprimode-induced apoptosis. Thus, humoral factors secreted by stromal cells protect MPN clones from JAK2 inhibitor therapy, clearly underscoring the importance of targeting the marrow niche in MPN for therapeutic purposes.
myeloproliferative neoplasms; JAK2(V617F); stromal cells; atiprimod; IL-6
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Podaci o prilogu
2010.
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objavljeno
Podaci o matičnoj publikaciji
Haematologica
Cazzola, Mario
Pavia: Ferrata Storti Foundation
0390-6078
Podaci o skupu
European Hematology Association
poster
10.06.2010-13.06.2010
Barcelona, Španjolska
Povezanost rada
Temeljne medicinske znanosti, Kliničke medicinske znanosti, Biologija