Show simple item record

dc.contributor.authorClaudiani, S
dc.contributor.authorMason, CC
dc.contributor.authorMilojkovic, D
dc.contributor.authorBianchi, A
dc.contributor.authorPellegrini, C
dc.contributor.authorDi Marco, A
dc.contributor.authorFiol, CR
dc.contributor.authorRobinson, M
dc.contributor.authorPonnusamy, K
dc.contributor.authorMokretar, K
dc.contributor.authorChowdhury, A
dc.contributor.authorAlbert, M
dc.contributor.authorReid, AG
dc.contributor.authorDeininger, MW
dc.contributor.authorNaresh, K
dc.contributor.authorApperley, JF
dc.contributor.authorKhorashad, JS
dc.date.accessioned2022-01-06T14:40:41Z
dc.date.available10000-01-01
dc.identifier.citationCancers, 13 (19), pp. 4863 - 4863
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4935
dc.identifier.eissn2072-6694
dc.identifier.doi10.3390/cancers13194863
dc.description.abstractAs the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a JAK2V617F-positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34+ cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients.
dc.format.extent4863 - 4863
dc.languageeng
dc.language.isoeng
dc.publisherMDPI AG
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleCarfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis
dc.typeJournal Article
dcterms.dateAccepted2021-09-20
rioxxterms.versionCVoR
rioxxterms.versionofrecord10.3390/cancers13194863
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancers
pubs.issue19
pubs.notesIndefinite
pubs.organisational-group/ICR
pubs.publication-statusPublished online
pubs.volume13
pubs.embargo.termsIndefinite
pubs.embargo.date10000-01-01
dc.contributor.icrauthorKhorashad, Jamshiden_US


Files in this item

Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0