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

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

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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	3670-3683
Number of pages	14
Journal	Oncogene
Volume	42
Issue number	50
Publication status	Published - 27 Oct 2023

Keywords

Child
Humans
Fingolimod Hydrochloride/pharmacology
Gene Expression Profiling
Leukemia, Myeloid, Acute/drug therapy
Myeloid-Lymphoid Leukemia Protein/genetics
Proteomics
Protein Phosphatase 2/drug effects

Access to Document

https://www.nature.com/articles/s41388-023-02840-1

Cite this

Di Mambro, A., Arroyo-Berdugo, Y., Fioretti, T., Randles, M., Cozzuto, L., Rajeeve, V., Cevenini, A., Austin, M. J., Esposito, G., Ponomarenko, J., Lucas, C. M., Cutillas, P., Gribben, J., Williams, O., Calle, Y., Patel, B., & Esposito, M. T. (2023). SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML. Oncogene, 42(50), 3670-3683. https://www.nature.com/articles/s41388-023-02840-1

@article{9dfe7a7efc4542ed8e889ee957366ec8,

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

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.",

keywords = "Child, Humans, Fingolimod Hydrochloride/pharmacology, Gene Expression Profiling, Leukemia, Myeloid, Acute/drug therapy, Myeloid-Lymphoid Leukemia Protein/genetics, Proteomics, Protein Phosphatase 2/drug effects",

author = "{Di Mambro}, Antonella and Yoana Arroyo-Berdugo and Tiziana Fioretti and Michael Randles and Luca Cozzuto and Vinothini Rajeeve and Armando Cevenini and Austin, {Michael J} and Gabriella Esposito and Julia Ponomarenko and Lucas, {Claire M} and Pedro Cutillas and John Gribben and Owen Williams and Yolanda Calle and Bela Patel and Esposito, {Maria Teresa}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = oct,

day = "27",

language = "English",

volume = "42",

pages = "3670--3683",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Nature Publishing Group",

number = "50",

}

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 2023, 'SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML', Oncogene, vol. 42, no. 50, pp. 3670-3683. <https://www.nature.com/articles/s41388-023-02840-1>

TY - JOUR

T1 - SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML

AU - Di Mambro, Antonella

AU - Arroyo-Berdugo, Yoana

AU - Fioretti, Tiziana

AU - Randles, Michael

AU - Cozzuto, Luca

AU - Rajeeve, Vinothini

AU - Cevenini, Armando

AU - Austin, Michael J

AU - Esposito, Gabriella

AU - Ponomarenko, Julia

AU - Lucas, Claire M

AU - Cutillas, Pedro

AU - Gribben, John

AU - Williams, Owen

AU - Calle, Yolanda

AU - Patel, Bela

AU - Esposito, Maria Teresa

PY - 2023/10/27

Y1 - 2023/10/27

N2 - 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.

AB - 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.

KW - Child

KW - Humans

KW - Fingolimod Hydrochloride/pharmacology

KW - Gene Expression Profiling

KW - Leukemia, Myeloid, Acute/drug therapy

KW - Myeloid-Lymphoid Leukemia Protein/genetics

KW - Proteomics

KW - Protein Phosphatase 2/drug effects

M3 - Article

C2 - 37891368

SN - 0950-9232

VL - 42

SP - 3670

EP - 3683

JO - Oncogene

JF - Oncogene

IS - 50

ER -