Reference Detail

Ref Type

Journal Article

PMID

(37891368)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Oncogene	42	50	2023 Dec	3670-3683	Oncogene

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KMT2A rearrange	acute myeloid leukemia	sensitive	Fingolimod	Preclinical - Cell culture	Actionable	In a preclinical study, Gilenya (fingolimod) inhibited proliferation and induced cell death and cell cycle arrest in an acute myeloid leukemia cell line harboring KMT2A rearrangement in culture (PMID: 37891368).	37891368
KMT2A rearrange	acute lymphoblastic leukemia	sensitive	Fingolimod	Preclinical - Cell culture	Actionable	In a preclinical study, Gilenya (fingolimod) inhibited proliferation and induced cell death and cell cycle arrest in an acute lymphoblastic leukemia cell line harboring KMT2A rearrangement in culture (PMID: 37891368).	37891368
KMT2A rearrange	acute myeloid leukemia	sensitive	Daunorubicin + Fingolimod	Preclinical - Patient cell culture	Actionable	In a preclinical study, treatment with the combination of Gilenya (fingolimod) and Cerubidine (daunorubicin) resulted in cell death in two acute myeloid leukemia cell lines harboring KMT2A rearrangements, and resulted in decreased colony formation in cells derived from a patient-derived xenograft (PDX) model in culture (PMID: 37891368)	37891368