Naslov
Bone marrow stroma-mediated paracrine inhibition of JAK2 inhibitor-induced apoptosis of JAK2V617F- mutated cells

Autori
Manshouri, Taghi ; Quintás-Cardama, Alfonso ; Estrov, Zeev ; Burger, Jan ; Livun, Ana ; Zhang, Ying ; Knez, Liza ; Harris, David ; Creighton, Chad ; Kantarjian, Hagop M. ; Verstovšek Srđan

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Haematologica, Abstract book / Cazzola, Mario - Pavia : Ferrata Storti Foundation, 2010

Skup
European Hematology Association

Mjesto i datum
Barcelona, Španjolska, 10.06.2010. - 13.06.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
myeloproliferative neoplasms; JAK2(V617F); stromal cells; atiprimod; IL-6

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Kliničke medicinske znanosti

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