Miembros del Grupo
Coordinador
Colaboradores
Irene
Peris Martínez
Líneas de Investigación
- Desarrollo de nuevas terapias combinadas en la leucemia mieloide aguda. Hacia un tratamiento personalizado en pacientes con sobreexpresión de la oncoproteína SET.
- Desarrollo de una nueva herramienta para la búsqueda de tratamientos antitumorales más eficaces empleando el modelo animal de pez cebra.
- Estudio de la oncoproteína SET como diana terapéutica en leucemia mieloide aguda.
- Mecanismos moleculares en el desarrollo y progresión de la leucemia mieloide aguda.
Palabras Clave
- Leucemia mieloide aguda
- PP2A
- SET
Publicaciones Científicas desde 2018
-
Autores: Marcotegui Arza, Nerea; Romero Murillo, Silvia; Marco Sanz, Javier; et al.Revista: CANCERSISSN: 2072-6694 Vol.15 N° 8 2023 págs. 2233ResumenInternal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia. These mutations cause constitutive activation of FLT3, altering the underlying signaling pathways and retaining FLT3 in the endoplasmic reticulum (ER). However, the mechanism that determines this peculiar localization is not fully understood. Here, we show that SET acts as a scaffold protein for nascent wild-type FLT3, facilitating its transport to the membrane. By contrast, the FLT3-ITD mutation impairs SET/FLT3 binding, leading to its retention in the ER. Of note, the tyrosine kinase inhibitor midostaurin promotes SET/FLT3 binding, increasing FLT3 in the membrane.The in-frame internal tandem duplication (ITD) of the FLT3 gene is an important negative prognostic factor in acute myeloid leukemia (AML). FLT3-ITD is constitutive active and partially retained in the endoplasmic reticulum (ER). Recent reports show that 3'UTRs function as scaffolds that can regulate the localization of plasma membrane proteins by recruiting the HuR-interacting protein SET to the site of translation. Therefore, we hypothesized that SET could mediate the FLT3 membrane location and that the FLT3-ITD mutation could somehow disrupt the model, impairing its membrane translocation. Immunofluorescence and immunoprecipitation assays demonstrated that SET and FLT3 co-localize and interact in FLT3-WT cells but hardly in FLT3-ITD. SET/FLT3 interaction occurs before FLT3 glycosylation. Furthermore, RNA immunoprecipitation in FLT3-WT cells confirmed that this interaction occurs through the binding of HuR to the 3'UTR of FLT3. HuR inhibition and SET nuclear retention reduced FLT3 in the membrane of FLT3-WT cells, indicating that both proteins are involved in FLT3 membrane trafficking. Interestingly, the FLT3 inhibitor midostaurin increases FLT3 in the membrane and SET/FLT3 binding. Therefore, our results show that SET is involved in the transport of FLT3-WT to the membrane; however, SET barely binds FLT3 in FLT3-ITD cells, contributing to its retention in the ER.
-
Autores: Pippa, R. (Autor de correspondencia); Odero, María D.Revista: CELLSISSN: 2073-4409 Vol.9 N° 3 2020 págs. 544ResumenThe 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.
-
Autores: Pippa, R. (Autor de correspondencia); Boffo, S.; Odero, María D.; et al.Revista: JOURNAL OF CELLULAR PHYSIOLOGYISSN: 0021-9541 Vol.235 N° 6 2020 págs. 5284 - 5292ResumenMesothelioma is an aggressive tumor that affects thousands of people every year. The therapeutic options for patients are limited; hence, a better understanding of mesothelioma biology is crucial to improve patient survival. To find new molecular targets and therapeutic strategies related to the protein phosphatase 2A (PP2A) network, we analyzed the gene expression of known PP2A inhibitors in mesothelioma patient samples. Our analysis disclosed a general overexpression of all PP2A-negative regulators in mesothelioma patients. Moreover, the expression of ANP32E and CIP2A genes, increased in 16% and 11% of cases, positively correlates with the ones of all the other PP2A regulators and the ones of the main cyclins and CDKs, suggesting the existence of a feed-forward loop that might contribute to the mesothelioma progression via PP2A inactivation. Overall, our study indicates the existence of a strategic and targetable axis between PP2A inhibitors (ANP32E and CIP2A) and cell cycle regulators (cyclin B2/CDK1) and provides a valuable rationale for using a personalized combinational therapy approach to improve mesothelioma patient survival.
-
Autores: Vicente Vázquez, Carmen (Autor de correspondencia); Arriazu Ruiz, Elena; Martinez-Balsalobre, E.; et al.Revista: CANCER LETTERSISSN: 0304-3835 Vol.468 2020 págs. 1 - 13ResumenAcute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5-15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2 A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in similar to 30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML. Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.
-
Autores: Arriazu Ruiz, Elena (Autor de correspondencia); Vicente Vázquez, Carmen; Pippa, R.; et al.Título: A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemiaRevista: BLOOD CANCER JOURNALISSN: 2044-5385 Vol.10 N° 1 2020ResumenAcute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38 beta is a common event in AML. We provide evidence that p38 beta potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38 beta/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.
-
Autores: Cendon-Florez, Y. ; Pippa, R. ; Boffo, S.; et al.Revista: CANCER RESEARCHISSN: 0008-5472 Vol.80 N° 16 2020
-
Autores: Perrotti, D. (Autor de correspondencia); Agarwal, A.; Lucas, C. M. ; et al.Revista: SCIENCE TRANSLATIONAL MEDICINEISSN: 1946-6234 Vol.11 N° 501 2019 págs. eaau0416
-
Autores: Broux, M. ; Prieto, C.; Demeyer, S.; et al.Revista: BLOODISSN: 0006-4971 Vol.134 N° 16 2019 págs. 1323 - 1336ResumenThe polycomb repressive complex 2, with core components EZH2, SUZ12, and EED, is responsible for writing histone 3 lysine 27 trimethylation histone marks associated with gene repression. Analysis of sequence data from 419 T-cell acute lymphoblastic leukemia (T-ALL) cases demonstrated a significant association between SUZ12 and JAK3 mutations. Here we show that CRISPR/Cas9-mediated inactivation of Suz12 cooperates with mutant JAK3 to drive T-cell transformation and T-ALL development. Gene expression profiling integrated with ChIP-seq and ATAC-seq data established that inactivation of Suz12 led to increased PI3K/mammalian target of rapamycin (mTOR), vascular endothelial growth factor (VEGF), and WNT signaling. Moreover, a drug screen revealed that JAK3/Suz12 mutant leukemia cells were more sensitive to histone deacetylase (HDAC)6 inhibition than JAK3 mutant leukemia cells. Among the broad genome and gene expression changes observed on Suz12 inactivation, our integrated analysis identified the PI3K/mTOR, VEGF/VEGF receptor, and HDAC6/HSP90 pathways as specific vulnerabilities in T-ALL cells with combined JAK3 and SUZ12 mutations.
-
Autores: Macias, R. I. R. (Autor de correspondencia); Sánchez-Martín, A.; Rodríguez-Macías, G.; et al.Revista: ONCOTARGETISSN: 1949-2553 2018
Proyectos desde 2018
-
Título: Caracterización del estrés oxidativo vascular en la fisiopatología de la diabetes: NADPH oxidasa 5 como potencial diana terapéuticaCódigo de expediente: 40/2021Investigador principal: GUILLERMO ZALBA GOÑI.Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUDConvocatoria: 2021 GN Proyectos de Investigación en saludFecha de inicio: 23-12-2021Fecha fin: 22-12-2024Importe concedido: 78.200,00€Otros fondos: -
-
Título: Mecanismos y eficacia de terapias combinadas basadas en la activación funcional de PP2A en leucemia mieloide aguda. Papel de las subunidades reguladoras PP2A como dianas terapéuticas.Código de expediente: PI20/01558Investigador principal: MARIA DOLORES ODERO DE DIOS, MARIA DOLORES ODERO DE DIOS.Financiador: INSTITUTO DE SALUD CARLOS IIIConvocatoria: 2020 AES Proyectos de investigaciónFecha de inicio: 01-01-2021Fecha fin: 31-12-2023Importe concedido: 268.620,00€Otros fondos: Fondos FEDER
-
Título: Xenoinjertos derivados de paciente en pez cebra: una nueva plataforma para la investigación traslacional en leucemia mieloide agudaCódigo de expediente: PI020 PDX-AMLInvestigador principal: MARIA DOLORES ODERO DE DIOS, MARIA DOLORES ODERO DE DIOS.Financiador: GOBIERNO DE NAVARRAConvocatoria: 2019 GN CentrosFecha de inicio: 07-09-2019Fecha fin: 30-11-2019Importe concedido: 59.184,43€Otros fondos: -
-
Título: Desarrollo de nuevas terapias combinadas en la leucemia mieloide aguda. Hacia un tratamiento personalizado en pacientes con sobreexpresión de la oncoproteina SETCódigo de expediente: PI17/02272Investigador principal: MARIA DOLORES ODERO DE DIOS, MARIA DOLORES ODERO DE DIOS.Financiador: INSTITUTO DE SALUD CARLOS IIIConvocatoria: AES2017 PROYECTOS DE INVESTIGACIÓNFecha de inicio: 01-01-2018Fecha fin: 31-12-2020Importe concedido: 147.620,00€Otros fondos: Fondos FEDER
-
Título: Estudio de la oncoproteína SET como diana terapéutica en leucemia mieloide aguda. Hacia un tratamiento personalizado mediante la combinación de activadores de la PP2A e inhibidores tirosinasa quinasas en pacientes con sobreexpresión de SETCódigo de expediente: 29/2015Investigador principal: MARIA DOLORES ODERO DE DIOS, MARIA DOLORES ODERO DE DIOS.Financiador: GOBIERNO DE NAVARRAConvocatoria: 2015 GN SALUDFecha de inicio: 06-12-2015Fecha fin: 05-12-2018Importe concedido: 47.510,00€Otros fondos: -
-
Título: Ayuda a Investigadores 2017 AECCInvestigador principal: MARIA DOLORES ODERO DE DIOS, MARIA DOLORES ODERO DE DIOSFinanciador: ASOCIACION ESPAÑOLA CONTRA EL CANCERConvocatoria: Investigador AECC 2018Fecha de inicio: 01-10-2018Fecha fin: 31-12-2022Importe concedido: 212.500,00€