Small-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasms
-
Altmetric Citations
Sonderegger, Stefan; Cerruti, Loretta; Tremblay, Cedric; Toulmin, Emma; Saw, Jesslyn; Nebl, Thomas; Hannan, Katherine; Lane, Steven W.; Falk, Hendrik; Unnikrishnan, Ashwin; Stupple, Paul
Description
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.author | Sonderegger, Stefan | |
---|---|---|
dc.contributor.author | Cerruti, Loretta | |
dc.contributor.author | Tremblay, Cedric | |
dc.contributor.author | Toulmin, Emma | |
dc.contributor.author | Saw, Jesslyn | |
dc.contributor.author | Nebl, Thomas | |
dc.contributor.author | Hannan, Katherine | |
dc.contributor.author | Lane, Steven W. | |
dc.contributor.author | Falk, Hendrik | |
dc.contributor.author | Unnikrishnan, Ashwin | |
dc.contributor.author | Stupple, Paul | |
dc.date.accessioned | 2021-12-02T23:05:07Z | |
dc.identifier.issn | 0006-4971 | |
dc.identifier.uri | http://hdl.handle.net/1885/254495 | |
dc.description.abstract | 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 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.mimetype | application/pdf | |
dc.language.iso | en_AU | |
dc.publisher | American Society of Hematology | |
dc.rights | © 2018 American Society of Hematology | |
dc.source | Blood | |
dc.title | Small-Molecule Inhibition of PRMT5 Induces Translational Stress and p53 in JAK2V617F Mutant Myeloproliferative Neoplasms | |
dc.type | Journal article | |
local.description.notes | Imported from ARIES | |
local.identifier.citationvolume | 132 | |
dc.date.issued | 2018 | |
local.identifier.absfor | 111201 - Cancer Cell Biology | |
local.identifier.ariespublication | u5517368xPUB2 | |
local.publisher.url | http://www.bloodjournal.org/ | |
local.type.status | Published Version | |
local.contributor.affiliation | Sonderegger, Stefan, Monash University | |
local.contributor.affiliation | Cerruti, Loretta, Monash University | |
local.contributor.affiliation | Tremblay, Cedric, Monash University | |
local.contributor.affiliation | Toulmin, Emma, Monash University | |
local.contributor.affiliation | Saw, Jesslyn, Monash University | |
local.contributor.affiliation | Nebl, Thomas, CSIRO | |
local.contributor.affiliation | Hannan, Kate, College of Health and Medicine, ANU | |
local.contributor.affiliation | Lane, Steven W., QIMR Berghofer Medical Research Institute | |
local.contributor.affiliation | Falk, Hendrik, Cancer Therapeutics CRC | |
local.contributor.affiliation | Unnikrishnan, Ashwin, University of New South Wales | |
local.contributor.affiliation | Stupple, Paul, Monash University | |
local.description.embargo | 2099-12-31 | |
local.bibliographicCitation.issue | Suppl 1 | |
local.bibliographicCitation.startpage | 53 | |
local.bibliographicCitation.lastpage | 53 | |
local.identifier.doi | 10.1182/blood-2018-99-118406 | |
local.identifier.absseo | 920102 - Cancer and Related Disorders | |
dc.date.updated | 2020-11-23T11:54:27Z | |
Collections | ANU Research Publications |
Download
File | Description | Size | Format | Image |
---|---|---|---|---|
01_Sonderegger_Small-Molecule_Inhibition_of_2018.pdf | 587.67 kB | Adobe PDF | Request a copy |
Items in Open Research are protected by copyright, with all rights reserved, unless otherwise indicated.
Updated: 17 November 2022/ Responsible Officer: University Librarian/ Page Contact: Library Systems & Web Coordinator