A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity

Vicente, Carmen; Arriazu, Elena; Martínez‐Balsalobre, Elena; Peris, Irene; Marcotegui, Nerea; García-Ramírez, Patricia; Pippa, Raffaella; Rabal, Obdulia; Oyarzábal, Julen; Guruceaga, Elizabeth; Prósper, Felipe; Mateos, M.C.; Cayuela, María L.; Odero, Marı́a D.

doi:10.1016/j.canlet.2019.10.007

Cited by 27 publications

(19 citation statements)

References 39 publications

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“…Treatment of engrafted leukemic blasts from patient 4 reflected the poor response during the treatment coarse. Zebrafish have received more attention during the last decade as an embryonic model host for xenografts, with nine publications exploring engraftment of other leukemic blast cell types to date [21,24,25,36,[38][39][40][41]. The ALL-ZeFiX assay both provides proof-of-principle for BCP-ALL exgraftment and extends the clinical utility of drug testing in immunosuppressed zebrafish avatars with quantifiable endpoint analysis and a 5-day assay format.…”

Section: Discussionmentioning

confidence: 99%

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Gauert

Olk

Pimentel-Gutiérrez

et al. 2020

Cancers

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Only half of patients with relapsed B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) currently survive with standard treatment protocols. Predicting individual patient responses to defined drugs prior to application would help therapy stratification and could improve survival. With the purpose to aid personalized targeted treatment approaches, we developed a human–zebrafish xenograft (ALL-ZeFiX) assay to predict drug response in a patient in 5 days. Leukemia blast cells were pericardially engrafted into transiently immunosuppressed Danio rerio embryos, and engrafted embryos treated for the test case, venetoclax, before single-cell dissolution for quantitative whole blast cell analysis. Bone marrow blasts from patients with newly diagnosed or relapsed BCP-ALL were successfully expanded in 60% of transplants in immunosuppressed zebrafish embryos. The response of BCP-ALL cell lines to venetoclax in ALL-ZeFiX assays mirrored responses in 2D cultures. Venetoclax produced varied responses in patient-derived BCP-ALL grafts, including two results mirroring treatment responses in two refractory BCP-ALL patients treated with venetoclax. Here we demonstrate proof-of-concept for our 5-day ALL-ZeFiX assay with primary patient blasts and the test case, venetoclax, which after expanded testing for further targeted drugs could support personalized treatment decisions within the clinical time window for decision-making.

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Section: Discussionmentioning

confidence: 99%

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Gauert

Olk

Pimentel-Gutiérrez

et al. 2020

Cancers

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“…We and others have determined that PP2A deregulation is a common event in AML patients, and the restoration of PP2A activity with PP2A activating drugs (PADs), such as FTY720, has potent antileukemic effects in AML cells, preventing cell growth and inducing caspase-dependent apoptosis [12,13,23,[26][27][28]. However, FTY720 induces cardio-toxicity at the anti-neoplastic dose.…”

Section: Protein Phosphatase 2amentioning

confidence: 99%

The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia

Marco¹,

Peris²,

Vicente³

et al. 2021

Acute Leukemias

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Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells characterized by the accumulation of several genetic and epigenetic mutations. Despite the progressive understanding of the molecular heterogeneity of the disease, the survival rate of patients older than 60 years old remains poor. Therefore, it is necessary to develop an effective treatment strategy for those patients in order to beat the disease and improve life quality. Reversible phosphorylation has been widely studied over the last years, and the deregulation of kinases and phosphatase have been verified to have a huge impact in leukemogenesis. Inactivation of the tumor-suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, constituting a promising target for cancer therapy. There are several PP2A inactivation mechanisms. However, overexpression of SET or cancerous inhibitors of PP2A, both endogenous inhibitors of PP2A, are recurrent events in AML patients, leading to the inactivation of the phosphatase PP2A. Preclinical studies show that PP2A reactivation using PP2A-activating drugs (PADs) manage to stop the development of the disease, and its combination with conventional chemotherapy and tyrosine kinase inhibitors have a synergistic cytotoxic effects. Recent studies have demonstrated that specifically activation of PP2A subunits, target crucial pathogenic drivers, increasing the efficacy of conventional treatments and opening new possibilities for personalized treatment in AML patients, especially in cases of PP2A deregulation. Here, we review the role of PP2A in AML as well as its drugable options.

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“…In AML, SET is highly dependent on MYC-transcriptional activity and recruitment of RUNX1 and GATA2 on its promoter [102]. By impairing SET binding to PP2A, with molecules like FTY720 [82,105], CM-1231 [106], or OP449 [107,108] it is possible to re-establish PP2A activity, inhibiting tumor growth [91,109] and overcoming therapeutic resistance in preclinical models [92,108]. SET is known to interact with SETBP1 (SET-binding protein 1), which protects SET from protease cleavage.…”

Section: Arpp19mentioning

confidence: 99%

“…PP2A-activating drugs are known to be highly effective in reducing MYC activity in several types of cancers [135][136][137]. Notably, small molecules that prevent SET-PP2A interaction such as FTY720, OP449, and CM-1231 re-activates PP2A, inhibiting cell proliferation and promoting apoptosis in AML and CML cell lines and primary patient samples [62,63,68,83,92,106,108,[138][139][140]. Combination of FTY720 or OP449 along with Idarubicin and Ara-C, drugs used in standard induction therapy in AML, or FLT3 inhibitors, as well as with tyrosine kinase inhibitors in CML, have a synergic effect and significantly reduced growth of leukemic cells [92,108,138,141].…”

Section: Targeting the Myc/pp2a Axis In Leukemiamentioning

confidence: 99%

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Pippa

Odero

2020

Cells

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The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

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A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity

Cited by 27 publications

References 39 publications

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

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