scholarly journals Splicing factor gene mutations in hematologic malignancies

Blood ◽  
2017 ◽  
Vol 129 (10) ◽  
pp. 1260-1269 ◽  
Author(s):  
Borja Saez ◽  
Matthew J. Walter ◽  
Timothy A. Graubert
Keyword(s):  
Animal Models ◽  
Messenger Rna ◽  
Gene Mutations ◽  
Hematologic Malignancies ◽  
Splicing Factor ◽  
Hematopoietic Malignancy ◽  
Healthy Elderly ◽  
Increased Risk ◽  
Recurrent Mutations ◽  
Clinical Consequences

Abstract Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway.

scholarly journals Splicing factor mutations in hematologic malignancies

Blood ◽  
2021 ◽  
Author(s):  
Sisi Chen ◽  
Salima Benbarche ◽  
Omar Abdel-Wahab
Keyword(s):  
Rna Splicing ◽  
Messenger Rna ◽  
Hematologic Malignancies ◽  
Splicing Factor ◽  
Splicing Factors ◽  
Loss Of Function ◽  
Genes Encoding ◽  
Precursor Rna ◽  
Early Phase Clinical Trials ◽  
Splicing Machinery

Mutations in genes encoding RNA splicing factors were discovered nearly ten years ago and are now understood to be amongst the most recurrent genetic abnormalities in patients with all forms of myeloid neoplasms and several types of lymphoproliferative disorders as well as subjects with clonal hematopoiesis. These discoveries implicate aberrant RNA splicing, the process by which precursor RNA is converted into mature messenger RNA, in the development of clonal hematopoietic conditions. Both the protein as well as the RNA components of the splicing machinery are affected by mutations at highly specific residues and a number of these mutations alter splicing in a manner distinct from loss of function. Importantly, cells bearing these mutations have now been shown to generate mRNA species with novel aberrant sequences, some of which may be critical to disease pathogenesis and/or novel targets for therapy. These findings have opened new avenues of research to understand biological pathways disrupted by altered splicing. In parallel, multiple studies have revealed that cells bearing change-of-function mutation in splicing factors are preferentially sensitized to any further genetic or chemical perturbations of the splicing machinery. These discoveries are now being pursued in several early phase clinical trials using molecules with diverse mechanisms of action. Here we review the molecular effects of splicing factor mutations on splicing, mechanisms by which these mutations drive clonal transformation of hematopoietic cells, and the development of new therapeutics targeting these genetic subsets of hematopoietic malignancies.

MSH2 splice site mutation and endometrial cancer

2006 ◽  
Vol 16 (3) ◽  
pp. 1419-1423 ◽  
Author(s):  
F. Bianchi ◽  
S. Rosati ◽  
L. Belvederesi ◽  
C. Loretelli ◽  
R. Catalani ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Splice Site ◽  
Messenger Rna ◽  
Germ Line ◽  
Cancer Susceptibility ◽  
Gene Mutations ◽  
Splice Site Mutation ◽  
Site Mutation ◽  
Msh2 Protein ◽  
Increased Risk

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited syndrome of cancer susceptibility caused by germ line mutations of genes participating in mismatch repair (MMR). Carriers of MMR gene mutations have an increased risk of colorectal cancers and cancer of other organs. Tumors of the endometrium represent the most frequent extracolonic malignancies in HNPCC. It has been suggested that women harboring MMR gene mutations have a higher risk of endometrial cancer than of colon cancer. Here, we describe an HNPCC patient with early-onset endometrial cancer and a strong familial history of endometrial tumors who harbored a germ line MSH2 splice site mutation (IVS9_2A>G). This mutation was responsible for abnormal messenger RNA processing, leading to the introduction of a premature stop signal and to the expression of a truncated MSH2 protein. In addition, the same mutation was associated with loss of MSH2 protein expression, high microsatellite instability, and PTEN inactivation. Although a direct relationship between the endometrial cancer susceptibility and the MSH2 mutation we found cannot be established, our observations, consistent with the work of other authors, suggest the involvement of germ line MSH2 abnormalities in endometrial tumor development and support the case for endometrial cancer screening in women from HNPCC families.

scholarly journals Inflammation-Related Carcinogenesis: Lessons from Animal Models to Clinical Aspects

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 921
Author(s):  
Futoshi Okada ◽  
Runa Izutsu ◽  
Keisuke Goto ◽  
Mitsuhiko Osaki
Keyword(s):  
Animal Models ◽  
Tissue Injury ◽  
Economic Status ◽  
Gene Mutations ◽  
Inflammatory Cells ◽  
The Body ◽  
Clinical Aspects ◽  
Promote Cell Proliferation ◽  
Organ Specific ◽  
Altered Gene

Inflammation-related carcinogenesis has long been known as one of the carcinogenesis patterns in humans. Common carcinogenic factors are inflammation caused by infection with pathogens or the uptake of foreign substances from the environment into the body. Inflammation-related carcinogenesis as a cause for cancer-related death worldwide accounts for approximately 20%, and the incidence varies widely by continent, country, and even region of the country and can be affected by economic status or development. Many novel approaches are currently available concerning the development of animal models to elucidate inflammation-related carcinogenesis. By learning from the oldest to the latest animal models for each organ, we sought to uncover the essential common causes of inflammation-related carcinogenesis. This review confirmed that a common etiology of organ-specific animal models that mimic human inflammation-related carcinogenesis is prolonged exudation of inflammatory cells. Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively. Inflammatory cytokines/growth factors released from inflammatory cells promote cell proliferation and repair tissue injury, and inflammation serves as a “carcinogenic niche”, because these fundamental biological events are common to all types of carcinogenesis, not just inflammation-related carcinogenesis. Since clinical strategies are needed to prevent carcinogenesis, we propose the therapeutic apheresis of inflammatory cells as a means of eliminating fundamental cause of inflammation-related carcinogenesis.

scholarly journals Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2974
Author(s):  
Haneen T. Salah ◽  
Courtney D. DiNardo ◽  
Marina Konopleva ◽  
Joseph D. Khoury
Keyword(s):  
Treatment Response ◽  
Gene Mutations ◽  
Hematologic Malignancies ◽  
Mechanisms Of Resistance ◽  
Apoptotic Pathway ◽  
Lymphoid Leukemia ◽  
Optimal Drug ◽  
Trisomy 12 ◽  
Apoptotic Pathways ◽  
Potential Biomarkers

Intrinsic apoptotic pathway dysregulation plays an essential role in all cancers, particularly hematologic malignancies. This role has led to the development of multiple therapeutic agents targeting this pathway. Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of chronic lymphoid leukemia and acute myeloid leukemia. Given the reported resistance to venetoclax, understanding the mechanisms of resistance and the potential biomarkers of response is crucial to ensure optimal drug usage and improved patient outcomes. Mechanisms of resistance to venetoclax include alterations involving the BH3-binding groove, BCL2 gene mutations affecting venetoclax binding, and activation of alternative anti-apoptotic pathways. Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

scholarly journals Preconceptional Resveratrol Supplementation Partially Counteracts Age-Related Reproductive Complications in C57BL/6J Female Mice

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1934
Author(s):  
Marta Ziętek ◽  
Katarzyna Barłowska ◽  
Barbara Wijas ◽  
Ewa Szablisty ◽  
Atanas G. Atanasov ◽  
...  
Keyword(s):  
Drinking Water ◽  
Animal Models ◽  
Mating Success ◽  
Pregnancy Outcomes ◽  
Pregnancy Complications ◽  
Polyphenolic Compound ◽  
Female Mice ◽  
Age Related ◽  
Increased Risk ◽  
Anti Oxidant

Aging is associated with a drastic decline in fertility/fecundity and with an increased risk of pregnancy complications. Resveratrol (RES), a natural polyphenolic compound, has shown anti-oxidant and anti-inflammatory activities in both human and animal models, thus representing a potential therapeutic and prophylactic anti-aging supplement. Here, we investigated whether preconceptional resveratrol supplementation improved reproductive outcomes in mid-aged (8-month-old) and old (12-month-old) C57BL/6J female mice. Female siblings were cohoused and assigned to either RES or vehicle supplementation to drinking water for 10 consecutive weeks. Subsequently, females were mated with non-supplemented males and their pregnancy outcomes were monitored. RES improved mating success in old, but not in mid-aged females, and prevented the occurrence of delivery complications in the latter. These results indicate that preconceptional RES supplementation could partially improve age-related reproductive complications, but it was not sufficient to restore fecundity in female mice at a very advanced age.

A controlled family study of late-onset non-affective psychosis (late paraphrenia)

1997 ◽  
Vol 170 (6) ◽  
pp. 511-514 ◽  
Author(s):  
R. J. Howard ◽  
C. Graham ◽  
P. Sham ◽  
J. Dennehey ◽  
D. J. Castle ◽  
...  
Keyword(s):  
At Risk ◽  
Late Onset ◽  
Psychiatric Morbidity ◽  
Late Life ◽  
Lifetime Risk ◽  
First Degree Relatives ◽  
Healthy Elderly ◽  
Increased Risk ◽  
Age Range ◽  
The Relationship

BackgroundThe relationship between those schizophrenia-like conditions that have their onset in late life and early-onset schizophrenia is unclear. Very few family history studies of patients with late-onset psychosis have been reported, and it is not known whether their relatives have an increased risk of psychosis.MethodInformation was collected on the psychiatric morbidity of 269 first-degree relatives of patients with schizophrenia or delusional disorder with an onset after the age of 60 (late paraphrenia), and 272 first-degree relatives of healthy elderly control subjects, using a research diagnostic instrument.ResultsWith a narrow age range (15–50 years) at risk, the estimated lifetime risk of schizophrenia was 1.3% in the relatives of both cases and controls. With a wider age range (15–90 years) at risk, estimated lifetime risk of schizophrenia was 2.3% for the relatives of cases, and 2.2% for the relatives of controls. However, depression was significantly more common among the relatives of cases than controls.ConclusionThose schizophrenia-like psychoses with onset in late life are not genetically associated with schizophrenia.

Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing

2015 ◽  
Vol 114 (09) ◽  
pp. 459-468 ◽  
Author(s):  
Susanne Gruber ◽  
Erik Grove ◽  
Thomas Weiss ◽  
Johann Wojta ◽  
Kurt Huber ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Platelet Reactivity ◽  
Platelet Inhibition ◽  
Antiplatelet Drugs ◽  
P2y12 Inhibitors ◽  
Reticulated Platelets ◽  
Increased Risk ◽  
Key Factor ◽  
Coronary Syndromes ◽  
Function Testing

SummaryPlatelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

Hepatic IGF1 DNA methylation is influenced by gender but not by intrauterine growth restriction in the young lamb

2015 ◽  
Vol 6 (6) ◽  
pp. 558-572 ◽  
Author(s):  
D. J. Carr ◽  
J. S. Milne ◽  
R. P. Aitken ◽  
C. L. Adam ◽  
J. M. Wallace
Keyword(s):  
Dna Methylation ◽  
Growth Hormone ◽  
Sexual Dimorphism ◽  
Mrna Expression ◽  
Intrauterine Growth Restriction ◽  
Messenger Rna ◽  
Methylation Status ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Increased Risk

Intrauterine growth restriction (IUGR) and postnatal catch-up growth confer an increased risk of adult-onset disease. Overnourishment of adolescent ewes generates IUGR in ∼50% of lambs, which subsequently exhibit increased fractional growth rates. We investigated putative epigenetic changes underlying this early postnatal phenotype by quantifying gene-specific methylation at cytosine:guanine (CpG) dinucleotides. Hepatic DNA/RNA was extracted from IUGR [eight male (M)/nine female (F)] and normal birth weight (12 M/9 F) lambs. Polymerase chain reaction was performed using primers targeting CpG islands in 10 genes: insulin, growth hormone, insulin-like growth factor (IGF)1, IGF2, H19, insulin receptor, growth hormone receptor, IGF receptors 1 and 2, and the glucocorticoid receptor. Using pyrosequencing, methylation status was determined by quantifying cytosine:thymine ratios at 57 CpG sites. Messenger RNA (mRNA) expression of IGF system genes and plasma IGF1/insulin were determined. DNA methylation was independent of IUGR status but sexual dimorphism in IGF1 methylation was evident (M<F, P=0.008). IGF1 mRNA:18S and plasma IGF1 were M>F (both P<0.001). IGF1 mRNA expression correlated negatively with IGF1 methylation (r=−0.507, P=0.002) and positively with plasma IGF1 (r=0.884, P<0.001). Carcass and empty body weights were greater in males (P=0.002–0.014) and this gender difference in early body conformation was mirrored by sexual dimorphism in hepatic IGF1 DNA methylation, mRNA expression and plasma IGF1 concentrations.

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