scholarly journals Splicing Anomalies in Myeloproliferative Neoplasms: Paving the Way for New Therapeutic Venues

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2216
Author(s):  
Marie Hautin ◽  
Clélia Mornet ◽  
Aurélie Chauveau ◽  
Delphine Bernard ◽  
Laurent Corcos ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Scientific Literature ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Mrna Splicing ◽  
Myelogenous Leukemia ◽  
Myeloid Malignancies ◽  
Clinical Series ◽  
Myeloid Leukemias ◽  
The Common

Since the discovery of spliceosome mutations in myeloid malignancies, abnormal pre-mRNA splicing, which has been well studied in various cancers, has attracted novel interest in hematology. However, despite the common occurrence of spliceosome mutations in myelo-proliferative neoplasms (MPN), not much is known regarding the characterization and mechanisms of splicing anomalies in MPN. In this article, we review the current scientific literature regarding “splicing and myeloproliferative neoplasms”. We first analyse the clinical series reporting spliceosome mutations in MPN and their clinical correlates. We then present the current knowledge about molecular mechanisms by which these mutations participate in the pathogenesis of MPN or other myeloid malignancies. Beside spliceosome mutations, splicing anomalies have been described in myeloproliferative neoplasms, as well as in acute myeloid leukemias, a dreadful complication of these chronic diseases. Based on splicing anomalies reported in chronic myelogenous leukemia as well as in acute leukemia, and the mechanisms presiding splicing deregulation, we propose that abnormal splicing plays a major role in the evolution of myeloproliferative neoplasms and may be the target of specific therapeutic strategies.

Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5556-5556
Author(s):  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Alla Abdulkadyrova ◽  
Vera Udaleva ◽  
Tatyana Zamotina ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Stratification ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Myeloproliferative Neoplasms ◽  
Population Analysis ◽  
Myelogenous Leukemia ◽  
Rank Test ◽  
Chronic Myeloproliferative Neoplasms

Abstract Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years. Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients' charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package. Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years). The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks` groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks' groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1. Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. Figure1 Overall survival in PMF patients according to DIPPS+ stratification groups. Figure1. Overall survival in PMF patients according to DIPPS+ stratification groups. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Impact of Epigenetic Modifications in Myeloid Malignancies

2021 ◽  
Vol 22 (9) ◽  
pp. 5013
Author(s):  
Deirdra Venney ◽  
Adone Mohd-Sarip ◽  
Ken I Mills
Keyword(s):  
Disease Progression ◽  
Dna Methyltransferase ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Myeloproliferative Neoplasms ◽  
Isocitrate Dehydrogenase 1 ◽  
Myeloid Malignancies ◽  
Broad Term ◽  
Critical Components ◽  
The Impact

Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies into genomic profiles of these diseases have shown 2000 somatic mutations prevalent across the spectrum of myeloid blood disorders. Epigenetic mutations are emerging as critical components of disease progression, with mutations in genes controlling chromatin regulation and methylation/acetylation status. Genes such as DNA methyltransferase 3A (DNMT3A), ten eleven translocation methylcytosine dioxygenase 2 (TET2), additional sex combs-like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2) and isocitrate dehydrogenase 1/2 (IDH1/2) show functional impact in disease pathogenesis. In this review we discuss how current knowledge relating to disease progression, mutational profile and therapeutic potential is progressing and increasing understanding of myeloid malignancies.

scholarly journals Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yujie Chen ◽  
Rafee Talukder ◽  
Brian Y. Merritt ◽  
Katherine Y. King ◽  
Marek Kimmel ◽  
...  
Keyword(s):  
Case Report ◽  
Molecular Mechanisms ◽  
Myeloproliferative Neoplasms ◽  
Lymphoblastic Leukemia ◽  
Genomic Data ◽  
Myelogenous Leukemia ◽  
Driver Mutations ◽  
Ancestral Reconstruction ◽  
Hematopoietic Stem ◽  
Molecular Abnormalities

Abstract Background We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration. Case presentation A 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation. Conclusions The use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.

Epigenetic Silencing of BRCA1 Is Linked to Homologous Recombination Repair Defects and Elevated Mir-155 Expression in Myeloid Neoplasms

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3525-3525
Author(s):  
Weijie Poh ◽  
Alison R Moliterno ◽  
Keith W. Pratz ◽  
Ivana Gojo ◽  
Michael A McDevitt ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Promoter Methylation ◽  
Myeloproliferative Neoplasms ◽  
Genetic Alterations ◽  
Epigenetic Silencing ◽  
Myelogenous Leukemia ◽  
Parp Inhibition ◽  
Brca1 Promoter ◽  
Myeloid Malignancies ◽  
Myeloid Neoplasms

Abstract Myeloid neoplasms are a heterogeneous group of clonal hematological disorders ranging from chronic myeloproliferative neoplasms (MPNs) to more aggressive mixed myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) and secondary acute myeloid leukemias (sAMLs). With the exception of BCR-ABL positive chronic myelogenous leukemia (CMLs), these diseases are clinically challenging to diagnose. Due to the clinical heterogeneity and lack of new biologic insights, current therapies fail to eradicate the malignant clone and alter the natural history of the disease. However, these diagnoses share overlapping features in morphologies, cytogenetics and genetic alterations suggesting common alterations in underlying disease pathways. We have previously reported genomic loss of HR genes in MPN patients linked to defective RAD51 foci induction and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition (McDevitt et al., ASH 2011). In this study, we directly examined homologous recombination (HR) in primary human samples by measuring induction of RAD51 foci after ionizing irradiation. Freshly isolated mononuclear leukocytes from patients diagnosed with MPNs, mixed MDS/MPNs and sAMLs were collected at the Johns Hopkins Hospital from April 2012 to March 2014. 11 of the 22 samples (50%) exhibited impaired RAD51 foci induction. With little evidence for biallelic genetic inactivation of HR genes in previous work, we evaluated promoter CpG island methylation of BRCA1, which we had previously found in a pilot study of myeloid neoplasm samples (McDevitt et al., ASH 2011). Using quantitative methylation-specific PCR (qMSP) with melt curve analysis, we reported BRCA1 promoter hypermethylation in 22 of 104 samples (21.2%), and observed statistically significant down-regulation of BRCA1 transcript in samples with BRCA1 CpG methylation (p<0.05). To determine the relationship between BRCA1 epigenetic silencing and HR status, we categorized BRCA1 gene expression of the samples according to the promoter methylation and HR status. Strikingly, we noted that all BRCA1 methylated samples were defective for HR and 5/12 (41.7%) of HR defective samples had down-regulated BRCA1 levels. We next validated the role of BRCA1 repression in vitro using the AML cell line OCI-AML3 using two independent shRNAs targeting BRCA1. We found that BRCA1-silenced cells have reduced induction of RAD51 foci, recapitulating our observations in primary samples with epigenetic silencing of BRCA1. Given the selective toxicity observed with HR-deficient cancers to PARP inhibition, we treated the BRCA1 knockdown cells with the PARP inhibitor ABT-888 and observed increased drug sensitivity. Finally, we examined additional consequences of BRCA1 loss in myeloid malignancies by investigating its role in repressing miR-155. Frequent up-regulation of miR-155 in leukemia is linked to poor prognosis, and its overexpression in murine models results in myeloproliferative disorders. Our results showed a statistically significant inverse correlation between BRCA1 and miR-155 expression in patient samples (Pearson r:-0.36; p-value<0.005). We also found elevated miR-155 expression in the BRCA1-silenced OCI-AML3 cells that increased during long-term BRCA1 repression. Our results demonstrate that defective HR repair occurs in a significant subset of myeloid malignancies. This provides a rationale for PARP inhibitors in this patient subpopulation who currently lack curative therapy, a strategy currently explored in two clinical studies (J0783, PI: Keith Pratz, MD; J1051, PI: Ivana Gojo, MD). Our finding showing BRCA1 promoter methylation in samples with defective HR highlights a novel mechanism underlying HR defects in myeloid malignancies, and offers a biomarker to identify potential responders to PARP inhibition. We also provide an alternative mechanism in which BRCA1 loss contributes to disease progression, via de-repressing miR-155 linked to aberrant expansion of myeloid cells. Disclosures No relevant conflicts of interest to declare.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

Natural products from the traditional Moroccan pharmacopoeia: A potential lead for the prevention and treatment of COVID-19

2020 ◽  
Vol 11 (SPL1) ◽  
pp. 1278-1285
Author(s):  
Mohamed Yafout ◽  
Amine Ousaid ◽  
Ibrahim Sbai El Otmani ◽  
Youssef Khayati ◽  
Amal Ait Haj Said
Keyword(s):  
Medicinal Plants ◽  
Plant Extracts ◽  
Molecular Mechanisms ◽  
Scientific Literature ◽  
Treatment Protocol ◽  
World Health ◽  
The World ◽  
Health Organization ◽  
Promising Source

The new SARS-CoV-2 belonging to the coronaviruses family has caused a pandemic affecting millions of people around the world. This pandemic has been declared by the World Health Organization as an international public health emergency. Although several clinical trials involving a large number of drugs are currently underway, no treatment protocol for COVID-19 has been officially approved so far. Here we demonstrate through a search in the scientific literature that the traditional Moroccan pharmacopoeia, which includes more than 500 medicinal plants, is a fascinating and promising source for the research of natural molecules active against SARS-CoV-2. Multiple in-silico and in-vitro studies showed that some of the medicinal plants used by Moroccans for centuries possess inhibitory activity against SARS-CoV or SARS-CoV-2. These inhibitory activities are achieved through the different molecular mechanisms of virus penetration and replication, or indirectly through stimulation of immunity. Thus, the potential of plants, plant extracts and molecules derived from plants that are traditionally used in Morocco and have activity against SARS-CoV-2, could be explored in the search for a preventive or curative treatment against COVID-19. Furthermore, safe plants or plant extracts that are proven to stimulate immunity could be officially recommended by governments as nutritional supplements.

Lighting a path: genetic studies pinpoint neurodevelopmental mechanisms in autism and related disorders

2012 ◽  
Vol 14 (3) ◽  
pp. 239-252
Keyword(s):  
Molecular Mechanisms ◽  
Protein Localization ◽  
Regulation Of Gene Expression ◽  
Neuronal Cell ◽  
Mrna Splicing ◽  
Genetic Mutations ◽  
Scaffolding Proteins ◽  
Molecular Processes ◽  
Genetic Studies ◽  
Novel Treatments

In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.

Alcohol Consumption and Risk of Uterine Fibroids

2020 ◽  
Vol 20 (4) ◽  
pp. 247-258 ◽  
Author(s):  
Hajra Takala ◽  
Qiwei Yang ◽  
Ahmed M. Abd El Razek ◽  
Mohamed Ali ◽  
Ayman Al-Hendy
Keyword(s):  
Alcohol Consumption ◽  
Animal Studies ◽  
Molecular Mechanisms ◽  
Legal Status ◽  
Current Knowledge ◽  
Uterine Fibroids ◽  
Future Directions ◽  
Working Adults ◽  
The Us ◽  
Alcohol Related Problems

Lifestyle factors, such as alcohol intake, have placed a substantial burden on public health. Alcohol consumption is increasing globally due to several factors including easy accessibility of this addictive substance besides its legal status and social acceptability. In the US, alcohol is the third leading preventable cause of death (after tobacco, poor diet and physical inactivity) with an estimated 88,000 people dying from alcohol-related causes annually, representing 1 in 10 deaths among working adults. Furthermore, the economic burden of excess drinking costs the US around $249 billion ($191.1 billion related to binge drinking). Although men likely drink more than women do, women are at much higher risk for alcohol-related problems. Alcohol use is also considered to be one of the most common non-communicable diseases, which affects reproductive health. This review article summarizes the current knowledge about alcohol-related pathogenesis of uterine fibroids (UFs) and highlights the molecular mechanisms that contribute to the development of UFs in response to alcohol consumption. Additionally, the effect of alcohol on the levels of various factors that are involved in UFs pathogenesis, such as steroid hormones, growth factors and cytokines, are summarized in this review. Animal studies of deleterious alcohol effect and future directions are discussed as well.

scholarly journals Molecular Mechanisms of Insulin Resistance in Polycystic Ovary Syndrome: Unraveling the Conundrum in Skeletal Muscle?

2019 ◽  
Vol 104 (11) ◽  
pp. 5372-5381 ◽  
Author(s):  
Nigel K Stepto ◽  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Kirsty A Walters ◽  
Raymond J Rodgers
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Polycystic Ovary Syndrome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Polycystic Ovary ◽  
Evidence Synthesis ◽  
Basic Research ◽  
Future Research ◽  
Ovary Syndrome

Abstract Context Polycystic ovary syndrome (PCOS) is a common endocrine condition affecting 8% to 13% of women across the lifespan. PCOS affects reproductive, metabolic, and mental health, generating a considerable health burden. Advances in treatment of women with PCOS has been hampered by evolving diagnostic criteria and poor recognition by clinicians. This has resulted in limited clinical and basic research. In this study, we provide insights into the current and future research on the metabolic features of PCOS, specifically as they relate to PCOS-specific insulin resistance (IR), that may affect the most metabolically active tissue, skeletal muscle. Current Knowledge PCOS is a highly heritable condition, yet it is phenotypically heterogeneous in both reproductive and metabolic features. Human studies thus far have not identified molecular mechanisms of PCOS-specific IR in skeletal muscle. However, recent research has provided new insights that implicate energy-sensing pathways regulated via epigenomic and resultant transcriptomic changes. Animal models, while in existence, have been underused in exploring molecular mechanisms of IR in PCOS and specifically in skeletal muscle. Future Directions Based on the latest evidence synthesis and technologies, researchers exploring molecular mechanisms of IR in PCOS, specifically in muscle, will likely need to generate new hypothesis to be tested in human and animal studies. Conclusion Investigations to elucidate the molecular mechanisms driving IR in PCOS are in their early stages, yet remarkable advances have been made in skeletal muscle. Overall, investigations have thus far created more questions than answers, which provide new opportunities to study complex endocrine conditions.

scholarly journals Immune Actions on the Peripheral Nervous System in Pain

2021 ◽  
Vol 22 (3) ◽  
pp. 1448
Author(s):  
Jessica Aijia Liu ◽  
Jing Yu ◽  
Chi Wai Cheung
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Process Integration ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Lipid Mediators ◽  
Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

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