Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/131690
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dc.contributor.authorTavakoli Shirazi, P.-
dc.contributor.authorEadie, L.N.-
dc.contributor.authorPage, E.C.-
dc.contributor.authorHeatley, S.L.-
dc.contributor.authorBruning, J.B.-
dc.contributor.authorWhite, D.L.-
dc.date.issued2021-
dc.identifier.citationCancer Letters, 2021; 512:28-37-
dc.identifier.issn0304-3835-
dc.identifier.issn1872-7980-
dc.identifier.urihttp://hdl.handle.net/2440/131690-
dc.description.abstractActivating TYK2-rearrangements have recently been identified and implicated in the leukemogenesis of high-risk acute lymphoblastic leukemia (HR-ALL) cases. Pre-clinical studies indicated the JAK/TYK2 inhibitor (JAKi), cerdulatinib, as a promising therapeutic against TYK2-rearranged ALL, attenuating the constitutive JAK/STAT signaling resulting from the TYK2 fusion protein. However, following a period of clinical efficacy, JAKi resistance often occurs resulting in relapse. In this study, we modeled potential mechanisms of JAKi resistance in TYK2-rearranged ALL cells in vitro in order to recapitulate possible clinical scenarios and provide a rationale for alternative therapies. Cerdulatinib resistant B-cells, driven by the MYB-TYK2 fusion oncogene, were generated by long-term exposure to the drug. Sustained treatment of MYB-TYK2-rearranged ALL cells with cerdulatinib led to enhanced and persistent JAK/STAT signaling, co-occurring with JAK1 overexpression. Hyperactivation of JAK/STAT signaling and JAK1 overexpression was reversible as cerdulatinib withdrawal resulted in re-sensitization to the drug. Importantly, histone deacetylase inhibitor (HDACi) therapies were efficacious against cerdulatinib-resistant cells demonstrating a potential alternative therapy for use in TYK2-rearranged B-ALL patients who have lost response to JAKi treatment regimens.-
dc.description.statementofresponsibilityPaniz Tavakoli Shirazi, Laura N.Eadie, Elyse C.Page, Susan L.Heatley, John B.Bruning, Deborah L.White-
dc.language.isoen-
dc.publisherElsevier-
dc.rights© 2021 Elsevier B.V. All rights reserved.-
dc.source.urihttp://dx.doi.org/10.1016/j.canlet.2021.04.027-
dc.subjectAcute lymphoblastic leukemia; TYK2 rearrangements; JAKi; resistance; HDACi-
dc.titleConstitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia-
dc.typeJournal article-
dc.identifier.doi10.1016/j.canlet.2021.04.027-
dc.relation.grantNHMRC-
pubs.publication-statusPublished-
dc.identifier.orcidTavakoli Shirazi, P. [0000-0002-1478-6660]-
dc.identifier.orcidEadie, L.N. [0000-0003-1912-7602]-
dc.identifier.orcidHeatley, S.L. [0000-0001-7497-6477]-
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]-
dc.identifier.orcidWhite, D.L. [0000-0003-4844-333X]-
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