Mecanismos moleculares en el desarrollo y progresión de la leucemia mieloide aguda

Grupos Investigadores

Miembros del Grupo

Coordinador

Odero , María D.

(modero@unav.es)

Investigadores

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

Publicaciones en Revistas

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Publicaciones en Revistas

Capítulos de Libros

Libros

Autores: Marcotegui Arza, Nerea; Romero Murillo, Silvia; Marco Sanz, Javier; et al.

Título: Set protein is involved in FLT3 membrane trafficking

Revista: CANCERS

ISSN: 2072-6694 Vol.15 N° 8 2023 págs. 2233

Resumen

Internal 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.

Título: The role of MYC and PP2A in the initiation and progression of myeloid leukemias

Revista: CELLS

ISSN: 2073-4409 Vol.9 N° 3 2020 págs. 544

Resumen

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.
Autores: Pippa, R. (Autor de correspondencia); Boffo, S.; Odero, María D.; et al.

Título: Data mining analysis of the PP2A cell cycle axis in mesothelioma patients

Revista: JOURNAL OF CELLULAR PHYSIOLOGY

ISSN: 0021-9541 Vol.235 N° 6 2020 págs. 5284 - 5292

Resumen

Mesothelioma 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.

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

Revista: CANCER LETTERS

ISSN: 0304-3835 Vol.468 2020 págs. 1 - 13

Resumen

Acute 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 leukemia

Revista: BLOOD CANCER JOURNAL

ISSN: 2044-5385 Vol.10 N° 1 2020

Resumen

Acute 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.

Título: Data mining analysis of the PP2A-cell cycle axis in breast and prostate cancer patients

Revista: CANCER RESEARCH

ISSN: 0008-5472 Vol.80 N° 16 2020
Autores: Perrotti, D. (Autor de correspondencia); Agarwal, A.; Lucas, C. M. ; et al.

Título: Comment on "PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL human leukemia"

Revista: SCIENCE TRANSLATIONAL MEDICINE

ISSN: 1946-6234 Vol.11 N° 501 2019 págs. eaau0416
Autores: Broux, M. ; Prieto, C.; Demeyer, S.; et al.

Título: Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia

Revista: BLOOD

ISSN: 0006-4971 Vol.134 N° 16 2019 págs. 1323 - 1336

Resumen

The 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.

Título: Role of drug transporters in the sensitivity of acute myeloid leukemia to sorafenib

Revista: ONCOTARGET

ISSN: 1949-2553 2018

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