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Bone Marrow Stromal Cells Reverse Proapoptotic Effects of JAK2 Inhibitor Atiprimod in Cells Carrying the JAK2V617F mutation (CROSBI ID 574754)

Prilog sa skupa u časopisu | sažetak izlaganja sa skupa | međunarodna recenzija

Manshouri, Taghi ; Estrov, Zeev ; Burger, Jan ; Livun, Ana ; Zhang, Ying ; Ma, Shuhuang ; Gaikwad, Amos ; Harris, David ; Kantarjian, Hagop M. ; Verstovšek, Srđan Bone Marrow Stromal Cells Reverse Proapoptotic Effects of JAK2 Inhibitor Atiprimod in Cells Carrying the JAK2V617F mutation // Blood / Dunbar, Cynthia E. (ur.). 2008

Podaci o odgovornosti

Manshouri, Taghi ; Estrov, Zeev ; Burger, Jan ; Livun, Ana ; Zhang, Ying ; Ma, Shuhuang ; Gaikwad, Amos ; Harris, David ; Kantarjian, Hagop M. ; Verstovšek, Srđan

engleski

Bone Marrow Stromal Cells Reverse Proapoptotic Effects of JAK2 Inhibitor Atiprimod in Cells Carrying the JAK2V617F mutation

Janus kinases (JAK) comprise a small family of cytoplasmic protein tyrosine kinases, which play an important role in the initiation of cytokine- triggered signaling events via signal transducer and activator of transcription (STAT) proteins. The recent reports of an activating somatic mutation in codon 617 of the JAK2 gene (JAK2V617F mutation) in patients with myeloproliferative disorders (MPDs), has opened new avenues for the development of targeted therapies for these malignancies and clinical trials with JAK2 inhibitors are underway. We report here the activity of Atiprimod (N, N- diethyl-8-dipropyl-2-azaspiro[4, 5]decane-2- propanamine), a novel compound with anti- inflammatory properties, in retrovirus-transduced JAK2V617F mutant-expressing murine FDCP-EpoR cells, set-2 cells, and blood cells from patients with polycythemia vera (PV). We compared the growth inhibitory effect of Atiprimod against two mouse FDCP cell lines transfected with erythropoietin receptor (Epo-R), and either wild- type JAK2WT or mutant JAK2V617F, and human megakaryoblastic leukemia cells with mutated JAK2V617F (set-2 cells). The growth inhibitory effect was assessed using 3-days MTS assay. Atiprimod was more potent against FDCP cells carrying mutant JAK2V617F cells (IC50 0.42 μM) and set-2 cells (IC50 0.53 μM) than FDCP wild-type JAK2WT cells (IC50 0.69 μM). Atiprimod inhibited the phosphorylation of JAK2 and downstream STAT3, STAT5, and AKT proteins in a dose- and time- dependent manner. It induced apoptosis, as evidenced by increase in mitochondrial membrane potential, caspase3 activity, and cleavage of PARP protein. The anti-proliferative effect on expanded PV patient progenitor’s cells was paralleled by a decrease in JAK2V617F mutant allele frequency in BFU-E or CFU-GM clones in clonogenic assay. However, co-culturing of JAK2V617F mutant cells with three different bone marrow stromal cell lines (Hs5, ABM-MSC, NK-Tert) either directly (cell on cell) or indirectly (separated by 0.4 μm micropore membranes) for 48 hours resulted in a significant protection of mutant cells from the effect of Atiprimod. Co-culturing of bone marrow stromal cells prevented Atiprimod (0.4 and 0.8 μM) induced apoptosis, and reversed the inhibition of phosphorylation of STAT proteins. Our results suggest that cytokines secreted by stromal cells might play an important role in protecting the hematopoietic cells from a JAK2 inhibitor. Further dissection of the nature of interactions between JAK2V617F mutant cells and marrow stromal cells may lead to new therapeutic avenues for patients with MPD.

JAK2(V617F) mutation; myeloproliferative neoplasms; atiprimod; STAT; stromal cells

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Podaci o prilogu

2008.

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objavljeno

Podaci o matičnoj publikaciji

Blood

Dunbar, Cynthia E.

Washington (MD): American Society of Hematology (ASH)

0006-4971

Podaci o skupu

American Society of Hematology

poster

06.12.2008-09.12.2008

San Francisco (CA), Sjedinjene Američke Države

Povezanost rada

Temeljne medicinske znanosti, Biologija

Indeksiranost