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1.
Expert Opin Investig Drugs ; 33(6): 561-573, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38687620

ABSTRACT

INTRODUCTION: Frontotemporal dementia (FTD) includes a group of neurodegenerative diseases characterized clinically by behavioral disturbances and by neurodegeneration of brain anterior temporal and frontal lobes, leading to atrophy. Apart from symptomatic treatments, there is, at present, no disease-modifying cure for FTD. AREAS COVERED: Three main mutations are known as causes of familial FTD, and large consortia have studied carriers of mutations, also in preclinical Phases. As genetic cases are the only ones in which the pathology can be predicted in life, compounds developed so far are directed toward specific proteins or mutations. Herein, recently approved clinical trials will be summarized, including molecules, mechanisms of action and pharmacological testing. EXPERT OPINION: These studies are paving the way for the future. They will clarify whether single mutations should be addressed rather than common proteins depositing in the brain to move from genetic to sporadic FTD.


Subject(s)
Frontotemporal Dementia , Mutation , Animals , Humans , Drug Development , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Frontotemporal Dementia/physiopathology , Frontotemporal Dementia/therapy
2.
Int J Mol Sci ; 24(18)2023 Sep 09.
Article in English | MEDLINE | ID: mdl-37762203

ABSTRACT

In an ever-increasing aged world, Alzheimer's disease (AD) represents the first cause of dementia and one of the first chronic diseases in elderly people. With 55 million people affected, the WHO considers AD to be a disease with public priority. Unfortunately, there are no final cures for this pathology. Treatment strategies are aimed to mitigate symptoms, i.e., acetylcholinesterase inhibitors (AChEI) and the N-Methyl-D-aspartate (NMDA) antagonist Memantine. At present, the best approaches for managing the disease seem to combine pharmacological and non-pharmacological therapies to stimulate cognitive reserve. Over the last twenty years, a number of drugs have been discovered acting on the well-established biological hallmarks of AD, deposition of ß-amyloid aggregates and accumulation of hyperphosphorylated tau protein in cells. Although previous efforts disappointed expectations, a new era in treating AD has been working its way recently. The Food and Drug Administration (FDA) gave conditional approval of the first disease-modifying therapy (DMT) for the treatment of AD, aducanumab, a monoclonal antibody (mAb) designed against Aß plaques and oligomers in 2021, and in January 2023, the FDA granted accelerated approval for a second monoclonal antibody, Lecanemab. This review describes ongoing clinical trials with DMTs and non-pharmacological therapies. We will also present a future scenario based on new biomarkers that can detect AD in preclinical or prodromal stages, identify people at risk of developing AD, and allow an early and curative treatment.


Subject(s)
Alzheimer Disease , United States , Humans , Aged , Alzheimer Disease/metabolism , Acetylcholinesterase , Amyloid beta-Peptides/metabolism , Memantine/therapeutic use , Memantine/pharmacology , Antibodies, Monoclonal/therapeutic use
3.
Int J Mol Sci ; 23(23)2022 Nov 25.
Article in English | MEDLINE | ID: mdl-36499048

ABSTRACT

Frontotemporal Dementia (FTD) represents a highly heritable neurodegenerative disorder. Most of the heritability is caused by autosomal dominant mutations in the Microtubule-Associated Protein Tau (MAPT), Progranulin (GRN), and the pathologic exanucleotide expansion of C9ORF72 genes. At the pathological level, either the tau or the TAR DNA-binding protein (TDP-43) account for almost all cases of FTD. Pathogenic mechanisms are just arising, and the emerging role of non-coding RNAs (ncRNAs), such as microRNAs (miRNA) and long non-coding RNAs (lncRNAs), have become increasingly evident. Using specific arrays, an exploratory analysis testing the expression levels of 84 miRNAs and 84 lncRNAs has been performed in a population consisting of 24 genetic FTD patients (eight GRN, eight C9ORF72, and eight MAPT mutation carriers), eight sporadic FTD patients, and eight healthy controls. The results showed a generalized ncRNA downregulation in patients carrying GRN and C9ORF72 when compared with the controls, with statistically significant results for the following miRNAs: miR-155-5p (Fold Change FC: 0.45, p = 0.037 FDR = 0.52), miR-15a-5p (FC: 0.13, p = 0.027, FDR = 1), miR-222-3p (FC: 0.13, p = 0.027, FDR = 0.778), miR-140-3p (FC: 0.096, p = 0.034, FRD = 0.593), miR-106b-5p (FC: 0.13, p = 0.02, FDR = 0.584) and an upregulation solely for miR-124-3p (FC: 2.1, p = 0.01, FDR = 0.893). Conversely, MAPT mutation carriers showed a generalized robust upregulation in several ncRNAs, specifically for miR-222-3p (FC: 22.3, p = 7 × 10-6, FDR = 0.117), miR-15a-5p (FC: 30.2, p = 0.008, FDR = 0.145), miR-27a-3p (FC: 27.8, p = 6 × 10-6, FDR = 0.0005), miR-223-3p (FC: 18.9, p = 0.005, FDR = 0.117), and miR-16-5p (FC: 10.9, p = 5.26 × 10-5, FDR = 0.001). These results suggest a clear, distinctive pattern of dysregulation among ncRNAs and specific enrichment gene pathways between mutations associated with the TDP-43 and tau pathologies. Nevertheless, these preliminary results need to be confirmed in a larger independent cohort.


Subject(s)
Frontotemporal Dementia , MicroRNAs , Pick Disease of the Brain , RNA, Long Noncoding , Humans , C9orf72 Protein/genetics , Frontotemporal Dementia/metabolism , MicroRNAs/genetics , Mutation , Pick Disease of the Brain/genetics , Progranulins/genetics , RNA, Long Noncoding/genetics , tau Proteins/genetics
4.
Biomedicines ; 10(10)2022 Oct 21.
Article in English | MEDLINE | ID: mdl-36289929

ABSTRACT

Recently, a fully automated instrument for the detection of the Cerebrospinal Fluid (CSF) biomarker for Alzheimer's disease (AD) (low concentration of Amyloid-beta 42 (Aß42), high concentration of total tau (T-tau) and Phosphorylated-tau (P-tau181)), has been implemented, namely CLEIA. We conducted a comparative analysis between ELISA and CLEIA methods in order to evaluate the analytical precision and the diagnostic performance of the novel CLEIA system on 111 CSF samples. Results confirmed a robust correlation between ELISA and CLEIA methods, with an improvement of the accuracy with the new CLEIA methodology in the detection of the single biomarkers and in their ratio values. For Aß42 regression analysis with Passing−Bablok showed a Pearson correlation coefficient r = 0.867 (0.8120; 0.907% 95% CI p < 0.0001), T-tau analysis: r = 0.968 (0.954; 0.978% 95% CI p < 0.0001) and P-tau181: r = 0.946 (0.922; 0.962 5% 95% CI p < 0.0001). The overall ROC AUC comparison between ROC in ELISA and ROC in CLEIA confirmed a more accurate ROC AUC with the new automatic method: T-tau AUC ELISA = 0.94 (95% CI 0.89; 0.99 p < 0.0001) vs. AUC CLEIA = 0.95 (95% CI 0.89; 1.00 p < 0.0001), and P-tau181 AUC ELISA = 0.91 (95% CI 0.85; 0.98 p < 0.0001) vs. AUC CLEIA = 0.98 (95% CI 0.95; 1.00 p < 0.0001). The performance of the new CLEIA method in automation is comparable and, for tau and P-tau181, even better, as compared with standard ELISA. Hopefully, in the future, automation could be useful in clinical diagnosis and also in the context of clinical studies.

5.
Biomedicines ; 10(9)2022 Sep 13.
Article in English | MEDLINE | ID: mdl-36140362

ABSTRACT

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson's disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

6.
Int J Mol Sci ; 23(8)2022 Apr 08.
Article in English | MEDLINE | ID: mdl-35456950

ABSTRACT

In the fascinating landscape of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are peeping out as a new promising and appreciated class of molecules with great potential as diagnostic and prognostic biomarkers. They come from circularization of single-stranded RNA molecules covalently closed and generated through alternative mRNA splicing. Dismissed for many years, similar to aberrant splicing by-products, nowadays, their role has been regained. They are able to regulate the expression of linear mRNA transcripts at different levels acting as miRNA sponges, interacting with ribonucleoproteins or exerting a control on gene expression. On the other hand, being extremely conserved across phyla and stable, cell and tissue specific, mostly abundant than the linear RNAs, it is not surprising that they should have critical biological functions. Curiously, circRNAs are particularly expressed in brain and they build up during aging and age-related diseases. These extraordinary peculiarities make circRNAs potentially suitable as promising molecular biomarkers, especially of aging and neurodegenerative diseases. This review aims to explore new evidence on circRNAs, emphasizing their role in aging and pathogenesis of major neurodegenerative disorders, Alzheimer's disease, frontotemporal dementia, and Parkinson's diseases with a look toward their potential usefulness in biomarker searching.


Subject(s)
MicroRNAs , Neurodegenerative Diseases , Biomarkers , Humans , MicroRNAs/genetics , Neurodegenerative Diseases/genetics , Neurogenesis/genetics , RNA, Circular/genetics , RNA, Messenger
7.
Int J Mol Sci ; 22(19)2021 Sep 27.
Article in English | MEDLINE | ID: mdl-34638725

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.


Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , DNA Repeat Expansion , Fibroblasts , Proteome , Signal Transduction/genetics , Skin , Adult , Aged , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , C9orf72 Protein/genetics , C9orf72 Protein/metabolism , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Male , Middle Aged , Proteome/genetics , Proteome/metabolism , Skin/metabolism , Skin/pathology
8.
Antioxidants (Basel) ; 10(9)2021 Aug 26.
Article in English | MEDLINE | ID: mdl-34572985

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-ß and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

9.
Cells ; 10(7)2021 07 08.
Article in English | MEDLINE | ID: mdl-34359903

ABSTRACT

Although extracellular vesicles (EVs) were initially relegated to a waste disposal role, nowadays, they have gained multiple fundamental functions working as messengers in intercellular communication as well as exerting active roles in physiological and pathological processes. Accumulating evidence proves the involvement of EVs in many diseases, including those of the central nervous system (CNS), such as multiple sclerosis (MS). Indeed, these membrane-bound particles, produced in any type of cell, carry and release a vast range of bioactive molecules (nucleic acids, proteins, and lipids), conferring genotypic and phenotypic changes to the recipient cell. This means that not only EVs per se but their content, especially, could reveal new candidate disease biomarkers and/or therapeutic agents. This review is intended to provide an overview regarding current knowledge about EVs' involvement in MS, analyzing the potential versatility of EVs as a new therapeutic tool and source of biomarkers.


Subject(s)
Biomarkers/metabolism , Extracellular Vesicles/metabolism , Multiple Sclerosis/metabolism , Multiple Sclerosis/therapy , Humans , Multiple Sclerosis/complications , Nerve Degeneration/complications , Nerve Degeneration/pathology , Neuroprotection
10.
Cells ; 9(6)2020 06 10.
Article in English | MEDLINE | ID: mdl-32531989

ABSTRACT

Small extracellular vesicles (EVs) are able to pass from the central nervous system (CNS) into peripheral blood and contain molecule markers of their parental origin. The aim of our study was to isolate and characterize total and neural-derived small EVs (NDEVs) and their micro RNA (miRNA) cargo in Alzheimer's disease (AD) patients. Small NDEVs were isolated from plasma in a population consisting of 40 AD patients and 40 healthy subjects (CTRLs) using high throughput Advanced TaqMan miRNA OpenArrays®, which enables the simultaneous determination of 754 miRNAs. MiR-23a-3p, miR-223-3p, miR-100-3p and miR-190-5p showed a significant dysregulation in small NDEVs from AD patients as compared with controls (1.16 ± 0.49 versus 7.54 ± 2.5, p = 0.026; 9.32 ± 2.27 versus 0.66 ± 0.18, p <0.0001; 0.069 ± 0.01 versus 0.5 ± 0.1, p < 0.0001 and 2.9 ± 1.2 versus 1.93 ± 0.9, p < 0.05, respectively). A further validation analysis confirmed that miR-23a-3p, miR-223-3p and miR-190a-5p levels in small NDEVs from AD patients were significantly upregulated as compared with controls (p = 0.008; p = 0.016; p = 0.003, respectively) whereas miR-100-3p levels were significantly downregulated (p = 0.008). This is the first study that carries out the comparison between total plasma small EV population and NDEVs, demonstrating the presence of a specific AD NDEV miRNA signature.


Subject(s)
Alzheimer Disease/genetics , MicroRNAs/blood , MicroRNAs/genetics , Aged , Alzheimer Disease/blood , Case-Control Studies , Extracellular Vesicles/genetics , Extracellular Vesicles/metabolism , Female , Genetic Profile , Humans , Male , Middle Aged
11.
Front Aging Neurosci ; 11: 232, 2019.
Article in English | MEDLINE | ID: mdl-31555123

ABSTRACT

Aging is consistently reported as the most important independent risk factor for neurodegenerative diseases. As life expectancy has significantly increased during the last decades, neurodegenerative diseases became one of the most critical public health problem in our society. The most investigated neurodegenerative diseases during aging are Alzheimer disease (AD), Frontotemporal Dementia (FTD) and Parkinson disease (PD). The search for biomarkers has been focused so far on cerebrospinal fluid (CSF) and blood. Recently, exosomes emerged as novel biological source with increasing interest for age-related neurodegenerative disease biomarkers. Exosomes are tiny Extracellular vesicles (EVs; 30-100 nm in size) released by all cell types which originate from the endosomal compartment. They constitute important vesicles for the release and transfer of multiple (signaling, toxic, and regulatory) molecules among cells. Initially considered with merely waste disposal function, instead exosomes have been recently recognized as fundamental mediators of intercellular communication. They can move from the site of release by diffusion and be retrieved in several body fluids, where they may dynamically reflect pathological changes of cells present in inaccessible sites such as the brain. Multiple evidence has implicated exosomes in age-associated neurodegenerative processes, which lead to cognitive impairment in later life. Critically, consolidated evidence indicates that pathological protein aggregates, including Aß, tau, and α-synuclein are released from brain cells in association with exosomes. Importantly, exosomes act as vehicles between cells not only of proteins but also of nucleic acids [DNA, mRNA transcripts, miRNA, and non-coding RNAs (ncRNAs)] thus potentially influencing gene expression in target cells. In this framework, exosomes could contribute to elucidate the molecular mechanisms underneath neurodegenerative diseases and could represent a promising source of biomarkers. Despite the involvement of exosomes in age-associated neurodegeneration, the study of exosomes and their genetic cargo in physiological aging and in neurodegenerative diseases is still in its infancy. Here, we review, the current knowledge on protein and ncRNAs cargo of exosomes in normal aging and in age-related neurodegenerative diseases.

12.
J Alzheimers Dis ; 69(3): 663-669, 2019.
Article in English | MEDLINE | ID: mdl-31156164

ABSTRACT

Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-ß CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.


Subject(s)
Aquaporin 4/cerebrospinal fluid , Glymphatic System/metabolism , Neurodegenerative Diseases/cerebrospinal fluid , Neurodegenerative Diseases/metabolism , Aged , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/cerebrospinal fluid , Female , Glymphatic System/physiopathology , Humans , Hydrocephalus, Normal Pressure/cerebrospinal fluid , Male , Neurodegenerative Diseases/physiopathology , tau Proteins/cerebrospinal fluid
13.
J Alzheimers Dis ; 67(4): 1173-1179, 2019.
Article in English | MEDLINE | ID: mdl-30689572

ABSTRACT

We report the case of two monozygotic twins with Thr272fs mutation in progranulin gene. Both patients developed frontotemporal dementia with 5 years difference in age at onset (Twin 1:73 years, Twin 2:68 years), with early behavioral, language, dysexecutive, and memory problems. They had the same formal education (5 years), but while Twin 1 dedicated more to social and leisure activity, Twin 2 worked all her life. At neuroimaging (MRI for Twin 1 and CT for Twin 2), they both showed asymmetric atrophy with left predominance. The two were discordant for total tau levels in cerebrospinal fluid, neuropsychological testing, and smoking habits. The description of the twins can help identify environmental factors that influence the onset and phenotype of frontotemporal dementia.


Subject(s)
Behavioral Symptoms , Brain , Frontotemporal Dementia , Progranulins/genetics , Aged , Atrophy , Behavioral Symptoms/diagnosis , Behavioral Symptoms/psychology , Brain/diagnostic imaging , Brain/pathology , Disease Progression , Epigenesis, Genetic , Female , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/genetics , Frontotemporal Dementia/psychology , Humans , Magnetic Resonance Imaging/methods , Mutation , Neuroimaging/methods , Neuropsychological Tests , Tomography, X-Ray Computed/methods , Twins, Monozygotic
14.
J Neuroimmunol ; 324: 129-135, 2018 11 15.
Article in English | MEDLINE | ID: mdl-30170791

ABSTRACT

LncRNA PCR arrays containing 90 common LncRNAs were used to screen lncRNA expression levels in PBMC from a discovery population of patients with MS. Data from discovery and replications cohorts showed a generalized dysregulation of lncRNA levels in MS patients compared with controls. MALAT1, MEG9, NRON, ANRIL, TUG1, XIST, SOX2OT, GOMAFU, HULC, BACE-1AS were significantly downregulated in MS patients in comparison with controls. Therefore, we performed a validation analysis in an independent cohort of Belgian origin. In this study, NRON and TUG1 downregulations in MS patients compared with controls were confirmed (p ≤ .05 and p ≤ .0001 respectively), whereas considering the other lncRNAs, the statistical threshold was not reached. LncRNAs profiling could thus represent a new challenge in the research of easy detectable biomarkers of disease susceptibility and progression.


Subject(s)
Leukocytes, Mononuclear/metabolism , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , RNA, Long Noncoding/biosynthesis , RNA, Long Noncoding/genetics , Transcriptome/physiology , Adult , Belgium/epidemiology , Biomarkers/metabolism , Cohort Studies , Female , Humans , Italy/epidemiology , Male , Middle Aged , Multiple Sclerosis/epidemiology
15.
Cancer Cell ; 32(1): 88-100.e6, 2017 07 10.
Article in English | MEDLINE | ID: mdl-28669490

ABSTRACT

Amplification of 1q21 occurs in approximately 30% of de novo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM.


Subject(s)
Multiple Myeloma/genetics , Nuclear Factor 45 Protein/physiology , RNA Splicing/genetics , DNA Damage , DNA Repair , Homologous Recombination , Humans , Nuclear Factor 45 Protein/genetics , Nuclear Factor 45 Protein/metabolism , Splicing Factor U2AF/metabolism , Tumor Cells, Cultured , Y-Box-Binding Protein 1/metabolism
16.
Leuk Res ; 39(8): 840-5, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26038121

ABSTRACT

ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B-lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up- and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status.


Subject(s)
Biomarkers, Tumor/genetics , Genes, Immunoglobulin Heavy Chain/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Mutation , Time-to-Treatment , Disease Progression , Follow-Up Studies , Gene Expression Profiling , Humans , Immunoglobulin Variable Region/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Predictive Value of Tests , Prognosis , Transcriptome , ZAP-70 Protein-Tyrosine Kinase/genetics
17.
Cancer Cell ; 27(5): 644-57, 2015 May 11.
Article in English | MEDLINE | ID: mdl-25965571

ABSTRACT

Myelodysplastic syndrome (MDS) risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly induces MDS is unknown. Here, we provide the genetic evidence that telomere dysfunction-induced DNA damage drives classical MDS phenotypes and alters common myeloid progenitor (CMP) differentiation by repressing the expression of mRNA splicing/processing genes, including SRSF2. RNA-seq analyses of telomere dysfunctional CMP identified aberrantly spliced transcripts linked to pathways relevant to MDS pathogenesis such as genome stability, DNA repair, chromatin remodeling, and histone modification, which are also enriched in mouse CMP haploinsufficient for SRSF2 and in CD34(+) CMML patient cells harboring SRSF2 mutation. Together, our studies establish an intimate link across telomere biology, aberrant RNA splicing, and myeloid progenitor differentiation.


Subject(s)
Cell Differentiation/genetics , Hematopoiesis/genetics , Myelodysplastic Syndromes/genetics , Telomere , Animals , Haploinsufficiency , Humans , Mice , Myelodysplastic Syndromes/pathology , Nuclear Proteins/genetics , RNA Splicing , Ribonucleoproteins/genetics , Serine-Arginine Splicing Factors
18.
PLoS One ; 10(3): e0118801, 2015.
Article in English | MEDLINE | ID: mdl-25786252

ABSTRACT

IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.


Subject(s)
Chromosomes, Human, Pair 12/genetics , Gene Expression Regulation, Neoplastic , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Receptor, Notch1/genetics , Receptors, Somatomedin/genetics , Trisomy/genetics , Clinical Trials as Topic , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, IGF Type 1
19.
Genes Chromosomes Cancer ; 53(2): 154-67, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24327544

ABSTRACT

We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells.


Subject(s)
Cell Line, Tumor/metabolism , Interleukin-6/metabolism , Multiple Myeloma/metabolism , Apoptosis , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor/pathology , Humans , Interleukin-6/genetics , Interleukin-6/pharmacology , MAP Kinase Signaling System , Multiple Myeloma/genetics , Multiple Myeloma/pathology , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Pyrazines/pharmacology , Signal Transduction , Transcriptome
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