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dc.contributor.authorBandara, Geethani
dc.contributor.authorMuñoz-Cano, Rosa
dc.contributor.authorTobío Ageitos, Araceli
dc.contributor.authorYin, Yuzhi
dc.contributor.authorKomarow, Hirsh D.
dc.contributor.authorDesai, Avanti
dc.contributor.authorMetcalfe, Dean D.
dc.contributor.authorOlivera, Ana
dc.date.accessioned2019-12-12T13:22:32Z
dc.date.available2019-12-12T13:22:32Z
dc.date.issued2018-03-28
dc.identifier.citationBandara G, Muñoz-Cano R, Tobío A, Yin Y, Komarow HD, Desai A, Metcalfe DD and Olivera A (2018) Targeting Sphingosine Kinase Isoforms Effectively Reduces Growth and Survival of Neoplastic Mast Cells With D816V-KIT. Front. Immunol. 9:631. doi: 10.3389/fimmu.2018.00631
dc.identifier.urihttp://hdl.handle.net/10347/20453
dc.description.abstractMastocytosis is a disorder resulting from an abnormal mast cell (MC) accumulation in tissues that is often associated with the D816V mutation in KIT, the tyrosine kinase receptor for stem cell factor. Therapies available to treat aggressive presentations of mastocytosis are limited, thus exploration of novel pharmacological targets that reduce MC burden is desirable. Since increased generation of the lipid mediator sphingosine-1-phosphate (S1P) by sphingosine kinase (SPHK) has been linked to oncogenesis, we studied the involvement of the two SPHK isoforms (SPHK1 and SPHK2) in the regulation of neoplastic human MC growth. While SPHK2 inhibition prevented entry into the cell cycle in normal and neoplastic human MCs with minimal effect on cell survival, SPHK1 inhibition caused cell cycle arrest in G2/M and apoptosis, particularly in D816V-KIT MCs. This was mediated via activation of the DNA damage response (DDR) cascade, including phosphorylation of the checkpoint kinase 2 (CHK2), CHK2-mediated M-phase inducer phosphatase 3 depletion, and p53 activation. Combination treatment of SPHK inhibitors with KIT inhibitors showed greater growth inhibition of D816V-KIT MCs than either inhibitor alone. Furthermore, inhibition of SPHK isoforms reduced the number of malignant bone marrow MCs from patients with mastocytosis and the growth of D816V-KIT MCs in a xenograft mouse model. Our results reveal a role for SPHK isoforms in the regulation of growth and survival in normal and neoplastic MCs and suggest a regulatory function for SPHK1 in the DDR in MCs with KIT mutations. The findings also suggest that targeting the SPHK/S1P axis may provide an alternative to tyrosine kinase inhibitors, alone or in combination, for the treatment of aggressive mastocytosis and other hematological malignancies associated with the D816V-KIT mutation
dc.description.sponsorshipThis work was supported by the Division of Intramural Research Programs within NIAID, at the National Institutes of Health. RM-C belongs to the Spanish Research Network ARADyAL RD16/0006/0007 of the Carlos III Health Institute and is a recipient of a Juan Rodes fellowship (Carlos II Health Institute JR16/00016)
dc.language.isoeng
dc.publisherFrontiers
dc.rights© 2018 Bandara, Muñoz-Cano, Tobío, Yin, Komarow, Desai, Metcalfe and Olivera. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms
dc.subjectSphingosine kinase
dc.subjectSphingosine kinase inhibitor
dc.subjectSphingosine-1-phosphate
dc.subjectMastocytosis
dc.subjectD816V
dc.subjectKIT
dc.subjectMast cells
dc.titleTargeting sphingosine kinase isoforms effectively reduces growth and survival of neoplastic mast cells with D816V-KIT
dc.typejournal article
dc.identifier.doi10.3389/fimmu.2018.00631
dc.relation.publisherversionhttps://doi.org/10.3389/fimmu.2018.00631
dc.type.hasVersionVoR
dc.identifier.essn1664-3224
dc.rights.accessRightsopen access
dc.contributor.affiliationUniversidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas
dc.description.peerreviewedSI


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