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

Di Mambro, Antonella ORCID: 0009-0003-1157-216X, Arroyo-Berdugo, Yoana ORCID: 0000-0003-3268-1616, Fioretti, Tiziana, Randles, Michael, Cozzuto, Luca, Rajeeve, Vinothini ORCID: 0000-0002-6361-4291, Cevenini, Armando, Austin, Michael J ORCID: 0000-0003-4218-0284, Esposito, Gabriella, Ponomarenko, Julia
et al (show 7 more authors) (2023) SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML. Oncogene, 42 (50). pp. 3670-3683.

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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.

Item Type: Article
Uncontrolled Keywords: Humans, Gene Expression Profiling, Proteomics, Child, Myeloid-Lymphoid Leukemia Protein, Leukemia, Myeloid, Acute, Protein Phosphatase 2, Fingolimod Hydrochloride
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 06 Feb 2024 11:14
Last Modified: 06 Feb 2024 11:14
DOI: 10.1038/s41388-023-02840-1
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