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1.
Leukemia ; 34(1): 100-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31197259

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.

2.
Oncogene ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616059

RESUMO

Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), particularly in NOTCH1-mutated patients. We provide first evidence that the Notch ligand DLL4 is a potent stimulator of Notch signaling in NOTCH1-mutated CLL cells while increases cell proliferation. Importantly, DLL4 is expressed in histiocytes from the lymph node, both in NOTCH1-mutated and -unmutated cases. We also show that the DLL4-induced activation of the Notch signaling pathway can be efficiently blocked with the specific anti-Notch1 antibody OMP-52M51. Accordingly, OMP-52M51 also reverses Notch-induced MYC, CCND1, and NPM1 gene expression as well as cell proliferation in NOTCH1-mutated CLL cells. In addition, DLL4 stimulation triggers the expression of protumor target genes, such as CXCR4, NRARP, and VEGFA, together with an increase in cell migration and angiogenesis. All these events can be antagonized by OMP-52M51. Collectively, our results emphasize the role of DLL4 stimulation in NOTCH1-mutated CLL and confirm the specific therapeutic targeting of Notch1 as a promising approach for this group of poor prognosis CLL patients.

3.
Haematologica ; 104(3): 576-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30262568

RESUMO

Mutations in genes of the RAS-BRAF-MAPK-ERK pathway have not been fully explored in patients with chronic lymphocytic leukemia. We, therefore, analyzed the clinical and biological characteristics of chronic lymphocytic leukemia patients with mutations in this pathway and investigated the in vitro response of primary cells to BRAF and ERK inhibitors. Putative damaging mutations were found in 25 of 452 patients (5.5%). Among these, BRAF was mutated in nine patients (2.0%), genes upstream of BRAF (KITLG, KIT, PTPN11, GNB1, KRAS and NRAS) were mutated in 12 patients (2.6%), and genes downstream of BRAF (MAPK2K1, MAPK2K2, and MAPK1) were mutated in five patients (1.1%). The most frequent mutations were missense, subclonal and mutually exclusive. Patients with these mutations more frequently had increased lactate dehydrogenase levels, high expression of ZAP-70, CD49d, CD38, trisomy 12 and unmutated immunoglobulin heavy-chain variable region genes and had a worse 5-year time to first treatment (hazard ratio 1.8, P=0.025). Gene expression analysis showed upregulation of genes of the MAPK pathway in the group carrying RAS-BRAF-MAPK-ERK pathway mutations. The BRAF inhibitors vemurafenib and dabrafenib were not able to inhibit phosphorylation of ERK, the downstream effector of the pathway, in primary cells. In contrast, ulixertinib, a pan-ERK inhibitor, decreased phospho-ERK levels. In conclusion, although larger series of patients are needed to corroborate these findings, our results suggest that the RAS-BRAF-MAPK-ERK pathway is one of the core cellular processes affected by novel mutations in chronic lymphocytic leukemia, is associated with adverse clinical features and could be pharmacologically inhibited.

4.
J Hematol Oncol ; 11(1): 112, 2018 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-30180865

RESUMO

BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive B-non-Hodgkin lymphoma with generally poor outcome. MCL is characterized by an aberrantly high cyclin D1-driven CDK4 activity. New molecular targeted therapies such as inhibitors of the ubiquitin-proteasome system (UPS) have shown promising results in preclinical studies and MCL patients. Our previous research revealed stabilization of the short-lived pro-apoptotic NOXA as a critical determinant for sensitivity to these inhibitors. It is currently unclear how cyclin D1 overexpression and aberrant CDK4 activity affect NOXA stabilization and treatment efficacy of UPS inhibitors in MCL. METHODS: The effect of cyclin D1-driven CDK4 activity on response of MCL cell lines and primary cells to proteasome inhibitor treatment was investigated using survival assays (Flow cytometry, AnnexinV/PI) and Western blot analysis of NOXA protein. Half-life of NOXA protein was determined by cycloheximide treatment and subsequent Western blot analysis. The role of autophagy was analyzed by LC3-II protein expression and autophagolysosome detection. Furthermore, silencing of autophagy-related genes was performed using siRNA and MCL cells were treated with autophagy inhibitors in combination with proteasome and CDK4 inhibition. RESULTS: In this study, we show that proteasome inhibitor-mediated cell death in MCL depends on cyclin D1-driven CDK4 activity. Inhibition of cyclin D1/CDK4 activity significantly reduced proteasome inhibitor-mediated stabilization of NOXA protein, mainly driven by an autophagy-mediated proteolysis. Bortezomib-induced cell death was significantly potentiated by compounds that interfere with autophagosomal function. Combined treatment with bortezomib and autophagy inhibitors enhanced NOXA stability leading to super-induction of NOXA protein. In addition to established autophagy modulators, we identified the fatty acid synthase inhibitor orlistat to be an efficient autophagy inhibitor when used in combination with bortezomib. Accordingly, this combination synergistically induced apoptosis both in MCL cell lines and in patient samples. CONCLUSION: Our data demonstrate that CDK4 activity in MCL is critical for NOXA stabilization upon treatment with UPS inhibitors allowing preferential induction of cell death in cyclin D transformed cells. Under UPS blocked conditions, autophagy appears as the critical regulator of NOXA induction. Therefore, inhibitors of autophagy are promising candidates to increase the activity of proteasome inhibitors in MCL.


Assuntos
Bortezomib/uso terapêutico , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Linfoma de Célula do Manto/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Autofagia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Humanos , Linfoma de Célula do Manto/patologia , Proteólise
5.
Expert Opin Drug Discov ; 12(10): 1041-1052, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28776453

RESUMO

INTRODUCTION: Next generation sequencing has provided a comprehensive understanding of the mutational landscape in chronic lymphocytic leukemia (CLL), and new drivers have been identified. Some of these drivers could be pharmacologically targeted to choose the most effective personalized therapy in each CLL patient. Areas covered: In this article, the authors uncover the potential role of new targeted therapies against the most recurrent mutations in CLL as well as the recently approved therapies. The authors also provide their expert opinion and give their perspectives for the future. Expert opinion: The development of more personalized therapies is of interest to clinicians as a system to enhance the duration of treatment response and to extend the survival and quality of life of CLL patients. The main challenge, however, will be to translate the preclinical results into the clinics. Therefore, the designing and execution of clinical trials focused on molecular drivers are the need of the hour.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Animais , Desenho de Drogas , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Terapia de Alvo Molecular , Mutação , Medicina de Precisão , Qualidade de Vida , Taxa de Sobrevida
6.
Optom Vis Sci ; 90(4): 335-43, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23376898

RESUMO

PURPOSE: To assess in a sample of normal, keratoconic, and keratoconus (KC) suspect eyes the performance of a set of new topographic indices computed directly from the digitized images of the Placido rings. METHODS: This comparative study was composed of a total of 124 eyes of 106 patients from the ophthalmic clinics Vissum Alicante and Vissum Almería (Spain) divided into three groups: control group (50 eyes), KC group (50 eyes), and KC suspect group (24 eyes). In all cases, a comprehensive examination was performed, including the corneal topography with a Placido-based CSO topography system. Clinical outcomes were compared among groups, along with the discriminating performance of the proposed irregularity indices. RESULTS: Significant differences at level 0.05 were found on the values of the indices among groups by means of Mann-Whitney-Wilcoxon nonparametric test and Fisher exact test. Additional statistical methods, such as receiver operating characteristic analysis and K-fold cross validation, confirmed the capability of the indices to discriminate between the three groups. CONCLUSIONS: Direct analysis of the digitized images of the Placido mires projected on the cornea is a valid and effective tool for detection of corneal irregularities. Although based only on the data from the anterior surface of the cornea, the new indices performed well even when applied to the KC suspect eyes. They have the advantage of simplicity of calculation combined with high sensitivity in corneal irregularity detection and thus can be used as supplementary criteria for diagnosing and grading KC that can be added to the current keratometric classifications.


Assuntos
Córnea/patologia , Topografia da Córnea/instrumentação , Ceratocone/diagnóstico , Programas de Rastreamento/métodos , Adulto , Desenho de Equipamento , Feminino , Seguimentos , Humanos , Incidência , Ceratocone/epidemiologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Espanha/epidemiologia
7.
Invest Ophthalmol Vis Sci ; 53(13): 8447-57, 2012 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-23169881

RESUMO

PURPOSE: We detected keratoconus cases with a significant potential for poor outcomes following intracorneal ring segment implantation (ICRS). We attempted to predict the potential of a case in terms of gain or loss of corrected distance visual acuity (CDVA). METHODS: In this retrospective and prospective, consecutive, nonrandomized, multicentric study, 58 keratoconic eyes (aged 1756) were implanted with the keraring using the femtosecond laser technology. The follow-up period was 6 months. keratometric, biomechanical, aberrometric, refractive, and visual variables were measured for two different groups: Group A included eyes that gained 0.2 or more in corrected distance visual acuity (CDVA, decimal scale) and group B included eyes that lost more than 0.15. Correlations between clinical parameters and changes in visual acuity were investigated. In addition, a linear regression model was developed using CDVA, apical keratometry (AK), and a new keratometric parameter defined and named by us as K-factor (K(F)). RESULTS: Significant differences between groups preoperatively were found for CDVA (P = 0.002), AK (P = 0.013), and K(F) (P = 0.025). The following predictive model was obtained using these variables: DeltaCDVA = -0.511 + 0.0007K(F)(p)-0.849CDVA(p)+0.008AK(p).$$ Predictability of the model was 0.797. Sensitivity was 88.1% and specificity 83.3%. CONCLUSIONS: The mathematical model predicts that this surgery is very effective in patients with preoperative CDVA (decimal scale) in the range of 0.01 to 0.3, predicting a gain of 3, 4, or even 5 lines. Gains are predicted and confirmed for CDVA between 0.3 and 0.5. For preoperative CDVA between 0.5 and 0.75 visual outcomes are doubtful. Higher values of CDVA often are related to a decrease in CDVA. This model may help surgeons to select the best cases for ICRS implantation and exclude the worst in terms of visual outcomes.


Assuntos
Substância Própria/cirurgia , Ceratocone/cirurgia , Modelos Teóricos , Próteses e Implantes , Implantação de Prótese , Acuidade Visual/fisiologia , Adolescente , Adulto , Substância Própria/fisiopatologia , Topografia da Córnea , Aberrações de Frente de Onda da Córnea/fisiopatologia , Feminino , Humanos , Ceratocone/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Refração Ocular/fisiologia , Estudos Retrospectivos , Adulto Jovem
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