Antiapoptotic proteins Bcl2 and BclX do not protect chronic myeloid leukemia cells from imatinib-mediated growth arrest

Imatinib (Glivec, Gleevec, STI571), a Bcr-Abl kinase inhibitor, is the most used drug in chronic myeloid leukemia. Imatinib induces apoptosis in a number of CML-derived cell lines, including K562. However, in order to achieve hematological remissions it is required chronic treatment with the drug, a fact inconsistent with a cytotoxic mechanism of imatinib in vivo. In this work we have analysed the effects of imatinib on the proliferation and apoptosis of K562-derived cell lines with constitutive expression of the anti-apoptotic genes Bcl2 and BclX. We found that imatinib-mediated apoptosis was completely abrogated in both Bcl2- and BclX-cell lines. However, imatinib inhibited proliferation, although growth rate was higher than in parental K562. We conclude that, besides its apoptotic effect, imatinib acts through an apoptosis-independent mechanism to arrest cell growth.The work was supported by grant PM98-0109 and SAF2002-04193 from Spanish Ministry of Science and Technology to J.L.Peer Reviewe

MYC in chronic myeloid leukemia: Induction of aberrant DNA synthesis and association with poor response to imatinib

El pdf es la versión post-print.-- et al.Untreated chronic myeloid leukemia (CML) progresses from chronic phase to blastic crisis (BC). Increased genomic instability, deregulated proliferation, and loss of differentiation appear associated to BC, but the molecular alterations underlying the progression of CML are poorly characterized. MYC oncogene is frequently deregulated in human cancer, often associated with tumor progression. Genomic instability and induction of aberrant DNA replication are described as effects of MYC. In this report, we studied MYC activities in CML cell lines with conditional MYC expression with and without exposure to imatinib, the front-line drug in CML therapy. In cells with conditional MYC expression, MYC did not rescue the proliferation arrest mediated by imatinib but provoked aberrant DNA synthesis and accumulation of cells with 4C content. We studied MYC mRNA expression in 66 CML patients at different phases of the disease, and we found that MYC expression was higher in CML patients at diagnosis than control bone marrows or in patients responding to imatinib. Further, high MYC levels at diagnosis correlated with a poor response to imatinib. MYC expression did not directly correlate with BCR-ABL levels in patients treated with imatinib. Overall our study suggests that, as in other tumor models, MYC-induced aberrant DNA synthesis in CML cells is consistent with MYC overexpression in untreated CML patients and nonresponding patients and supports a role for MYC in CML progression, possibly through promotion of genomic instability. ©2011 AACR.This work was supported by a grant from the Ministerio de Ciencia e Innovacion of Spain (SAF08-01581) and by the RTICC (Red Temática de Investigación Cooperativa en Cancer, RD06/0020/0017) to J. León and a grant from Instituto de Salud Carlos III (FIS08/0829) to M.D. Delgado.Peer Reviewe

Colorectal adenomas contain multiple somatic mutations that do not coincide with synchronous adenocarcinoma specimens

We have performed a comparative ultrasequencing study of multiple colorectal lesions obtained simultaneously from four patients. Our data show that benign lesions (adenomatous or hyperplastic polyps) contain a high mutational load. Additionally multiple synchronous colorectal lesions show non overlapping mutational signatures highlighting the degree of heterogeneity between multiple specimens in the same patient. Observations in these cases imply that considering not only the number of mutations but an effective oncogenic combination of mutations can determine the malignant progression of colorectal lesions

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

© The Author(s) 2019.A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.This work was supported by: SAF2016-76046-R and SAF2013-46292-R (MINECO and FEDER) to B.C.F., PI16/00156 (isciii and FEDER) to J.P.V., LUCHAMOS POR LA VIDA project to F.R.J. and J.P.V., SAF2017-83702-R (MINECO and FEDER), Red TERCEL RD12/0019/0024 (ISCIII) and GVA-PROMETEO 2018/041 (Generalitat Valenciana) to S.M. J.P.V. is supported by the RyC research programme (RYC-2013-14097) and F.R.J. by the predoctoral research programme (BES-2014-070615), from MINECO and FEDER

Impact of a Primary Care Antimicrobial Stewardship Program on Bacterial Resistance Control and Ecological Imprint in Urinary Tract Infections

Antimicrobial stewardship programs (ASPs) are a central component in reducing the overprescription of unnecessary antibiotics, with multiple studies showing benefits in the reduction of bacterial resistance. Less commonly, ASPs have been performed in outpatient settings, but there is a lack of available data in these settings. We implemented an ASP in a large regional outpatient setting to assess its feasibility and effectiveness. Over a 5-year post-implementation period, compared to the pre-intervention period, a significant reduction in antibiotic prescription occurred, with a reduction in resistance in E. coli urinary isolates. ASP activities also were found to be cost-effective, with a reduction in medication prescription

The Biodiversity of the Mediterranean Sea: Estimates, Patterns, and Threats

The Mediterranean Sea is a marine biodiversity hot spot. Here we combined an extensive literature analysis with expert opinions to update publicly available estimates of major taxa in this marine ecosystem and to revise and update several species lists. We also assessed overall spatial and temporal patterns of species diversity and identified major changes and threats. Our results listed approximately 17,000 marine species occurring in the Mediterranean Sea. However, our estimates of marine diversity are still incomplete as yet—undescribed species will be added in the future. Diversity for microbes is substantially underestimated, and the deep-sea areas and portions of the southern and eastern region are still poorly known. In addition, the invasion of alien species is a crucial factor that will continue to change the biodiversity of the Mediterranean, mainly in its eastern basin that can spread rapidly northwards and westwards due to the warming of the Mediterranean Sea. Spatial patterns showed a general decrease in biodiversity from northwestern to southeastern regions following a gradient of production, with some exceptions and caution due to gaps in our knowledge of the biota along the southern and eastern rims. Biodiversity was also generally higher in coastal areas and continental shelves, and decreases with depth. Temporal trends indicated that overexploitation and habitat loss have been the main human drivers of historical changes in biodiversity. At present, habitat loss and degradation, followed by fishing impacts, pollution, climate change, eutrophication, and the establishment of alien species are the most important threats and affect the greatest number of taxonomic groups. All these impacts are expected to grow in importance in the future, especially climate change and habitat degradation. The spatial identification of hot spots highlighted the ecological importance of most of the western Mediterranean shelves (and in particular, the Strait of Gibraltar and the adjacent Alboran Sea), western African coast, the Adriatic, and the Aegean Sea, which show high concentrations of endangered, threatened, or vulnerable species. The Levantine Basin, severely impacted by the invasion of species, is endangered as well

p73 cooperates with Ras in the activation of MAP kinase signaling cascade

The p73 gene is capable of inducing cell cycle arrest, apoptosis, senescence, differentiation and to cooperate with oncogenic Ras in cellular transformation. Ras can be considered as a branch point in signal transduction, where diverse extracellular stimuli converge. The intensity of the mitogen-activated protein kinase (MAPK) cascade activation influences the cellular response to Ras. Despite the fundamental role of p53 in Ras-induced growth arrest and senescence, it remains unclear how the Ras/MEK/ERK pathway induces growth arrest in the absence of p53. We report here that oncogenic Ras stabilizes p73 resulting in p73 accumulation and enhancement of its activity. p73, in turn, induces a sustained activation of the MAP kinase cascade synergizing with oncogenic Ras. We also found that inhibition of p73 function modifies the cellular outcome to Ras activation inhibiting Ras-dependent differentiation. Here, we show for the first time that there is a signaling loop between Ras-dependent MAPK cascade activation and p73 function.BFG has a fellowship from Consejería de Educación y Cultura de la Junta de Castilla y León and Fondo Social Europeo. MHV and JPV are recipients of predoctoral fellowships from the Spanish Ministerio de Educación y Ciencia. FMG has a fellowship from the University of León, Spain. This work was supported by Grants SAF-4193CO2 and SAF-4193CO1 from the Spanish Ministerio de Educación y Ciencia to MCM and JLS, respectively.Peer reviewe

Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton.Peer Reviewe

c-myc expression in cell lines derived from chronic myeloid leukemia

Letter to the Editor.-- Open AccessWe analyzed proliferation and c-myc expression in three chronic myeloid leukemia (CML)-derived cell lines treated with interferon-α, hydroxyurea, busulfan and imatinib. We found that c-Myc levels did not universally correlate with CML cell proliferation and that c-Myc down-regulation correlated to imatinib activity but not to imatinib-induced apoptosis.This study was supported by grants SAF2002-04193 from Spanish Ministry of Science and Technology to J.L., and FIS01-1129 from Spanish Ministry of Health to M.D.D.Peer Reviewe

Activation of Ras and Rho GTPases and MAP Kinases by G-Protein-Coupled Receptors

14 páginas, 2 figuras.A complex intracellular signaling network mediates the multiple biological activities of G-protein-coupled receptors (GPCRs). Among them, monomeric GTPases and a family of closely related proline-targeted serine–threonine kinases, collectively known as Mitogen-Activated Protein Kinases (MAPKs), appears to play central roles in orchestrating the proliferative responses to multiple mitogens that act on GPCRs. Upon GDP/GTP exchange, monomeric GTPases control the phosphorylation of conserved threonine and tyrosine residues in MAPKs by their immediate upstream kinases, increasing their enzymatic activity and inducing their translocation to the nucleus where they phosphorylate transcription factors, thereby regulating the expression of genes playing a key role in normal and aberrant cell growth. Recently, a number of GPCRs have been engineered to provide exclusive activation by synthetic drug-like compounds while becoming insensitive to endogenous ligands. These engineered receptors, named Receptors Activated Solely by Synthetic Ligands (RASSLs), promise better understanding of GPCRs signaling in vitro and in vivo, thus representing ideal tools to selectively modulate MAPK signaling routes controlling a wide range of biological functions, from proliferation to differentiation, migration, invasion, and cell survival or death by apoptosis.Peer reviewe