Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/131690
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Tavakoli Shirazi, P. | - |
dc.contributor.author | Eadie, L.N. | - |
dc.contributor.author | Page, E.C. | - |
dc.contributor.author | Heatley, S.L. | - |
dc.contributor.author | Bruning, J.B. | - |
dc.contributor.author | White, D.L. | - |
dc.date.issued | 2021 | - |
dc.identifier.citation | Cancer Letters, 2021; 512:28-37 | - |
dc.identifier.issn | 0304-3835 | - |
dc.identifier.issn | 1872-7980 | - |
dc.identifier.uri | http://hdl.handle.net/2440/131690 | - |
dc.description.abstract | Activating 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.statementofresponsibility | Paniz Tavakoli Shirazi, Laura N.Eadie, Elyse C.Page, Susan L.Heatley, John B.Bruning, Deborah L.White | - |
dc.language.iso | en | - |
dc.publisher | Elsevier | - |
dc.rights | © 2021 Elsevier B.V. All rights reserved. | - |
dc.source.uri | http://dx.doi.org/10.1016/j.canlet.2021.04.027 | - |
dc.subject | Acute lymphoblastic leukemia; TYK2 rearrangements; JAKi; resistance; HDACi | - |
dc.title | Constitutive JAK/STAT signaling is the primary mechanism of resistance to JAKi in TYK2-rearranged acute lymphoblastic leukemia | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1016/j.canlet.2021.04.027 | - |
dc.relation.grant | NHMRC | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Tavakoli Shirazi, P. [0000-0002-1478-6660] | - |
dc.identifier.orcid | Eadie, L.N. [0000-0003-1912-7602] | - |
dc.identifier.orcid | Heatley, S.L. [0000-0001-7497-6477] | - |
dc.identifier.orcid | Bruning, J.B. [0000-0002-6919-1824] | - |
dc.identifier.orcid | White, D.L. [0000-0003-4844-333X] | - |
Appears in Collections: | Aurora harvest 4 Medicine publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.