Small-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasms

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dc.contributor.authorSonderegger, Stefan
dc.contributor.authorCerruti, Loretta
dc.contributor.authorTremblay, Cedric
dc.contributor.authorToulmin, Emma
dc.contributor.authorSaw, Jesslyn
dc.contributor.authorNebl, Thomas
dc.contributor.authorHannan, Katherine
dc.contributor.authorLane, Steven W.
dc.contributor.authorFalk, Hendrik
dc.contributor.authorUnnikrishnan, Ashwin
dc.contributor.authorStupple, Paul
dc.date.accessioned2021-12-02T23:05:07Z
dc.date.issued2018
dc.date.updated2020-11-23T11:54:27Z
dc.description.abstractBackground: Myeloproliferative neoplasms (MPN) are a diverse group of hematopoietic stem cell disorders. JAK2V617F gain-of-function is the most prevalent mutation, accounting for more than 60% of MPNs. PRMT5 was initially identified as a JAK-binding protein. Its enzymatic function catalyses the symmetric di-methylation of arginine on a variety of substrates, including histones and proteins of the splicing apparatus. It has been proposed that mutant JAK2 can phosphorylate PRMT5, leading to loss of methylation activity and promotion of erythropoiesis (Liu F. et al. Cancer Cell 2011). Based upon this study, it was proposed that enhancing PRMT5 activity may be a useful therapeutic measure (Skoda RC et al. Cancer Cell 2011). Aim: To determine the role of PRMT5 in JAK2V671F mutant hematopoiesis. Hypothesis: Inhibition of PRMT5 will exacerbate JAK2V617F hematopoiesis Results: Using a conditional null allele, we deleted Prmt5 in embryonic development with the hematopoietic-specific VavCre transgene. This led to embryonic lethality at E9.5 due to absence of erythropoiesis but not other lineages. Similar embryonic lethality was observed using the erythroid specific EpoRCre transgene.en_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn0006-4971en_AU
dc.identifier.urihttp://hdl.handle.net/1885/254495
dc.language.isoen_AUen_AU
dc.publisherAmerican Society of Hematologyen_AU
dc.rights© 2018 American Society of Hematologyen_AU
dc.sourceBlooden_AU
dc.titleSmall-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasmsen_AU
dc.typeJournal articleen_AU
local.bibliographicCitation.issueSuppl 1en_AU
local.bibliographicCitation.lastpage53en_AU
local.bibliographicCitation.startpage53en_AU
local.contributor.affiliationSonderegger, Stefan, Monash Universityen_AU
local.contributor.affiliationCerruti, Loretta, Monash Universityen_AU
local.contributor.affiliationTremblay, Cedric, Monash Universityen_AU
local.contributor.affiliationToulmin, Emma, Monash Universityen_AU
local.contributor.affiliationSaw, Jesslyn, Monash Universityen_AU
local.contributor.affiliationNebl, Thomas, CSIROen_AU
local.contributor.affiliationHannan, Kate, College of Health and Medicine, ANUen_AU
local.contributor.affiliationLane, Steven W., QIMR Berghofer Medical Research Instituteen_AU
local.contributor.affiliationFalk, Hendrik, Cancer Therapeutics CRCen_AU
local.contributor.affiliationUnnikrishnan, Ashwin, University of New South Walesen_AU
local.contributor.affiliationStupple, Paul, Monash Universityen_AU
local.contributor.authoremailu1000189@anu.edu.auen_AU
local.contributor.authoruidHannan, Kate, u1000189en_AU
local.description.embargo2099-12-31
local.description.notesImported from ARIESen_AU
local.identifier.absfor111201 - Cancer Cell Biologyen_AU
local.identifier.absseo920102 - Cancer and Related Disordersen_AU
local.identifier.ariespublicationu5517368xPUB2en_AU
local.identifier.citationvolume132en_AU
local.identifier.doi10.1182/blood-2018-99-118406en_AU
local.identifier.uidSubmittedByu5517368en_AU
local.publisher.urlhttp://www.bloodjournal.org/en_AU
local.type.statusPublished Versionen_AU

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