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

Sonderegger, Stefan; Cerruti, Loretta; Tremblay, Cedric; Toulmin, Emma; Saw, Jesslyn; Nebl, Thomas; Hannan, Katherine; Lane, Steven W.; Falk, Hendrik; Unnikrishnan, Ashwin; Stupple, Paul

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Background: 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...[Show more]

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.identifier.issn0006-4971
dc.identifier.urihttp://hdl.handle.net/1885/254495
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.
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherAmerican Society of Hematology
dc.rights© 2018 American Society of Hematology
dc.sourceBlood
dc.titleSmall-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasms
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume132
dc.date.issued2018
local.identifier.absfor111201 - Cancer Cell Biology
local.identifier.ariespublicationu5517368xPUB2
local.publisher.urlhttp://www.bloodjournal.org/
local.type.statusPublished Version
local.contributor.affiliationSonderegger, Stefan, Monash University
local.contributor.affiliationCerruti, Loretta, Monash University
local.contributor.affiliationTremblay, Cedric, Monash University
local.contributor.affiliationToulmin, Emma, Monash University
local.contributor.affiliationSaw, Jesslyn, Monash University
local.contributor.affiliationNebl, Thomas, CSIRO
local.contributor.affiliationHannan, Kate, College of Health and Medicine, ANU
local.contributor.affiliationLane, Steven W., QIMR Berghofer Medical Research Institute
local.contributor.affiliationFalk, Hendrik, Cancer Therapeutics CRC
local.contributor.affiliationUnnikrishnan, Ashwin, University of New South Wales
local.contributor.affiliationStupple, Paul, Monash University
local.description.embargo2099-12-31
local.bibliographicCitation.issueSuppl 1
local.bibliographicCitation.startpage53
local.bibliographicCitation.lastpage53
local.identifier.doi10.1182/blood-2018-99-118406
local.identifier.absseo920102 - Cancer and Related Disorders
dc.date.updated2020-11-23T11:54:27Z
CollectionsANU Research Publications

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