- Title
- Shwachman-Bodian-Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia
- Creator
- Dun, Matthew D.; Mannan, Abdul; Germon, Zacary; Faulkner, Sam; Chi, Mengna; Skerrett-Byrne, David; Murray, Heather C.; Flanagan, Hayley; Almazi, Juhura G.; Hondermarck, Hubert; Nixon, Brett; De Iuliis, Geoff; Rigby, Callum J.; Chamberlain, J; Alvaro, F; de Bock, CE; Morris, JC; Enjeti, Anoop K.; Verrills, Nicole M.; Butler, Stephen; Toop, Hamish D.; Beck, Dominik; Connerty, Patrick; Sillar, Jonathan; Kahl, Richard G. S.; Duchatel, Ryan J.
- Relation
- Leukemia Vol. 34, Issue 12, p. 3393-3397
- Publisher Link
- http://dx.doi.org/10.1038/s41375-020-0814-0
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2020
- Description
- The family of serine/threonine phosphatases (PP2A) frequently shows reduced activity in myeloid leukaemias [1, 2]. This is particularly the case in acute myeloid leukaemias (AML) driven by overexpression or constitutively active c-KIT and FLT3, where PP2A inhibition is required for cell transformation which enhances the activation of oncogenic signalling pathways and promotes anti-apoptotic processes [2,3,4]. In myeloid malignancies, pharmacological activation of PP2A using Forskolin, the immunosuppressant FTY720 (reviewed in [2]) and the non-immunosuppressive chiral-deoxy analogue of FTY720, AAL(S) has a potential therapeutic benefit [4, 5]. FTY720 is the most well-characterised PP2A-activating compound and phosphorylated by SPHK2 in vivo [6]. FTY720-P acts as a high-affinity agonist for four of the five G protein-coupled sphingosine-1-phosphate receptors (S1PR), causing receptor internalisation and increased activity of the JAK2–PI3Kγ–PKC signalling axis, a common molecular driver of myeloproliferative neoplasms [7]. Phosphorylation has been shown to be dispensable for the anti-leukaemic activity of FTY720 [4, 5]. Furthermore, dose-limiting toxicities are associated with S1PR activation at the anti-neoplastic dose (FTY720-P) [8]. Non-phosphorylated FTY720 binds to the nuclear proto-oncogene SET in leukaemia cells, driving PP2A activity and apoptosis [9]. Non-phosphorylatable analogues of FTY720 also inhibit proliferation and induce apoptosis in several cancer cell lines including AML cell lines and patient samples through the activation of PP2A [5]. However, the molecular targets of these novel chemicals are unknown.
- Subject
- acute myeloid leukaemia; oncogenes; protein phosphatase; protein; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1444610
- Identifier
- uon:42359
- Identifier
- ISSN:0887-6924
- Language
- eng
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