SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

Di Mambro, Antonella; Arroyo-Berdugo, Yoana; Fioretti, Tiziana; Randles, Michael; Cozzuto, Luca; Rajeeve, Vinothini; Cevenini, Armando; Austin, Michael J.; Esposito, Grabiella; Ponomarenko, Julia; Lucas, Claire M.; Cutillas, Pedro; Gribben, John; Williams, Owen; Calle, Yolanda; Patel, Bela; Esposito, Maria Teresa

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

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dc.contributor.author Di Mambro, Antonella
dc.contributor.author Arroyo-Berdugo, Yoana
dc.contributor.author Fioretti, Tiziana
dc.contributor.author Randles, Michael
dc.contributor.author Cozzuto, Luca
dc.contributor.author Rajeeve, Vinothini
dc.contributor.author Cevenini, Armando
dc.contributor.author Austin, Michael J.
dc.contributor.author Esposito, Grabiella
dc.contributor.author Ponomarenko, Julia
dc.contributor.author Lucas, Claire M.
dc.contributor.author Cutillas, Pedro
dc.contributor.author Gribben, John
dc.contributor.author Williams, Owen
dc.contributor.author Calle, Yolanda
dc.contributor.author Patel, Bela
dc.contributor.author Esposito, Maria Teresa
dc.date.accessioned 2024-01-23T07:24:22Z
dc.date.available 2024-01-23T07:24:22Z
dc.date.issued 2023
dc.description.abstract KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3β, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.
dc.format.mimetype application/pdf
dc.identifier.citation Di Mambro A, Arroyo-Berdugo Y, Fioretti T, Randles M, Cozzuto L, Rajeeve V, Cevenini A, Austin MJ, Esposito G, Ponomarenko J, Lucas CM, Cutillas P, Gribben J, Williams O, Calle Y, Patel B, Esposito MT. SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML. Oncogene. 2023 Dec;42(50):3670-83. DOI: 10.1038/s41388-023-02840-1
dc.identifier.doi http://dx.doi.org/10.1038/s41388-023-02840-1
dc.identifier.issn 0950-9232
dc.identifier.uri http://hdl.handle.net/10230/58805
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Oncogene. 2023 Dec;42(50):3670-83
dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Acute myeloid leukaemia
dc.subject.keyword Cell signalling
dc.subject.keyword Paediatric cancer
dc.subject.keyword Proteomics
dc.subject.keyword Transcriptomics
dc.title SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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