Gene Summary

Gene:U2AF1; U2 small nuclear RNA auxiliary factor 1
Aliases: RN, FP793, U2AF35, U2AFBP, RNU2AF1
Summary:This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:splicing factor U2AF 35 kDa subunit
Source:NCBIAccessed: 13 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • RNA Splicing Factors
  • Splicing Factor U2AF
  • DNA Methylation
  • Cohort Studies
  • Acute Myeloid Leukaemia
  • U2AF1
  • RNA Splicing
  • Disease Progression
  • Follow-Up Studies
  • Adolescents
  • DNA-Binding Proteins
  • Ribonucleoproteins
  • Childhood Cancer
  • Epigenetics
  • Single Nucleotide Polymorphism
  • Cancer Gene Expression Regulation
  • Lung Cancer
  • Transcription Factors
  • Mutation
  • Survival Rate
  • DNA Mutational Analysis
  • Neoplastic Cell Transformation
  • Chronic Myelogenous Leukemia
  • Chromosome 21
  • Proto-Oncogene Proteins
  • Haematological Malignancies
  • Phosphoproteins
  • Ribonucleoprotein, U2 Small Nuclear
  • Spliceosomes
  • Serine-Arginine Splicing Factors
  • Young Adult
  • Signal Transduction
  • Repressor Proteins
  • Messenger RNA
  • Nuclear Proteins
  • Alternative Splicing
  • Infant
  • Chronic Myelomonocytic Leukemia
  • Mutation Rate
  • Genetic Association Studies
  • Myelodysplastic Syndromes
  • High-Throughput Nucleotide Sequencing
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: U2AF1 (cancer-related)

Shen Q, Lin F, Rong X, et al.
Temporal Cerebral Microbleeds Are Associated With Radiation Necrosis and Cognitive Dysfunction in Patients Treated for Nasopharyngeal Carcinoma.
Int J Radiat Oncol Biol Phys. 2016; 94(5):1113-20 [PubMed] Related Publications
PURPOSE: Radiation therapy for patients with nasopharyngeal carcinoma (NPC) may be complicated with radiation-induced brain necrosis (RN), resulting in deteriorated cognitive function. However, the underlying mechanism of this phenomenon remains unclear. This study attempts to elucidate the association between cerebral microbleeds (CMBs) and radiation necrosis and cognitive dysfunction in NPC patients treated with radiation therapy.
METHODS AND MATERIALS: This cross-sectional study included 106 NPC patients who were exposed to radiation therapy (78 patients with RN and 28 without RN). Sixty-six patients without discernable intracranial pathology were included as the control group. CMBs were confirmed using susceptibility-weighted magnetic resonance imaging. Cognitive function was accessed using Montreal Cognitive Assessment. Patients with a total score below 26 were defined as cognitively dysfunction.
RESULTS: Seventy-seven patients (98.7%) in the RN group and 12 patients (42.9%) in the non-RN group had at least 1 CMB. In contrast, only 14 patients (21.2%) in the control group had CMBs. In patients with a history of radiation therapy, CMBs most commonly presented in temporal lobes (76.4%) followed by cerebellum (23.7%). Patients with RN had more temporal CMBs than those in the non-RN group (37.7 ± 51.9 vs 3.8 ± 12.6, respectively; P<.001). The number of temporal lobe CMBs was predictive for larger volume of brain necrosis (P<.001) in multivariate linear regression analysis. Although cognitive impairment was diagnosed in 55.1% of RN patients, only 7.1% of non-RN patients sustained cognitive impairment (P<.001). After adjusting for age, sex, education, period after radiation therapy, CMBs in other lobes, and RN volume, the number of temporal CMBs remained an independent risk factor for cognitive dysfunction (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.01-1.04; P=.003).
CONCLUSIONS: CMBs is a common radiological manifestation in NPC patients with RN. The number of temporal CMBs is independently associated with increased likelihood of cognitive dysfunction in patients with RN.

Ibáñez M, Carbonell-Caballero J, García-Alonso L, et al.
The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.
PLoS One. 2016; 11(2):e0148346 [PubMed] Free Access to Full Article Related Publications
Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

Marques SC, Ranjbar B, Laursen MB, et al.
High miR-34a expression improves response to doxorubicin in diffuse large B-cell lymphoma.
Exp Hematol. 2016; 44(4):238-46.e2 [PubMed] Related Publications
The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) is the immunochemotherapy-based R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone). Resistance to treatment, intrinsic or acquired, is observed in approximately 40% of patients with DLBCL, who thus require novel interventions to survive. To identify biomarkers for cytotoxic response assessment, microRNAs (miRNAs) associated with doxorubicin sensitivity were determined by combining global miRNA expression profiling with systematic dose-response screens in 15 human DLBCL cell lines. One candidate, miR-34a, was tested in functional in vitro studies and in vivo in a retrospective clinical cohort. High expression of miR-34a was observed in cell lines sensitive to doxorubicin, and upregulation of miR-34a is documented here to increase doxorubicin sensitivity in in vitro lentiviral transduction assays. High expression of miR-34a had a prognostic impact using overall survival as outcome. With risk stratification of DLBCL samples based on resistance gene signatures (REGS), doxorubicin-responsive samples had statistically significant upregulated miR-34a expression. Classification of the DLBCL samples into subset-specific B cell-associated gene signatures (BAGS) revealed differentiation-specific expression of miR-34a. Our data further support FOXP1 as a target of miR-34a, suggesting that downregulation of FOXP1 may sensitize DLBCL cells to doxorubicin. We conclude that miRNAs, in particular miR-34a, may have clinical utility in DLBCL patients as both predictive and prognostic biomarkers.

Hou HA, Liu CY, Kuo YY, et al.
Splicing factor mutations predict poor prognosis in patients with de novo acute myeloid leukemia.
Oncotarget. 2016; 7(8):9084-101 [PubMed] Free Access to Full Article Related Publications
Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but the prognostic relevance of these genes mutations in acute myeloid leukemia (AML) remains unclear. In this study, we investigated mutations of three SF genes, SF3B1, U2AF1 and SRSF2, by Sanger sequencing in 500 patients with de novo AML and analysed their clinical relevance. SF mutations were identified in 10.8% of total cohort and 13.2% of those with intermediate-risk cytogenetics. SF mutations were closely associated with RUNX1, ASXL1, IDH2 and TET2 mutations. SF-mutated AML patients had a significantly lower complete remission rate and shorter disease-free survival (DFS) and overall survival (OS) than those without the mutation. Multivariate analysis demonstrated that SFmutation was an independent poor prognostic factor for DFS and OS. A scoring system incorporating SF mutation and ten other prognostic factors was proved very useful to risk-stratify AML patients. Sequential study of paired samples showed that SF mutations were stable during AML evolution. In conclusion, SF mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. These mutations may be potential targets for novel treatment and biomarkers for disease monitoring in AML.

de Melo JT, de Souza Timoteo AR, Lajus TB, et al.
XPC deficiency is related to APE1 and OGG1 expression and function.
Mutat Res. 2016 Feb-Mar; 784-785:25-33 [PubMed] Related Publications
Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.

Hamilton BK, Visconte V, Jia X, et al.
Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations.
Am J Hematol. 2016; 91(4):406-9 [PubMed] Related Publications
Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations in the spliceosomal genes (U2AF1 and SRSF2) predict for poor outcomes in myelodysplastic syndromes (MDS) and related diseases. We investigated the effect of hematopoietic cell transplant (HCT) on the negative prognostic impact of U2AF1 and SRSF2 mutations. In total, 122 patients with MDS (30%), acute myeloid leukemia (51%), myeloproliferative neoplasms (MPN) (11%), and MDS/MPN (8%) receiving a HCT from 2003 to 2012 were evaluated for mutations in U2AF1 and SRSF2 by direct sequencing. Median time of follow up was 24 months (range 0.46-110). SRSF2 mutations were detected in 11 (10%) patients and U2AF1 in 3 (3%) patients. There were no significant differences in baseline characteristics between mutated and wild-type (WT) patients. Patients carrying SRSF2 and U2AF1 mutations had similar overall survival (P = 0.84), relapse mortality (P = 0.50), and non-relapse mortality (P = 0.72) compared to WT patients. However, taking into account disease status and cytogenetics in a subset of AML patients, SRSF2 and U2AF1 mutations were associated with worse survival (HR 3.71, P = 0.035).

Vad-Nielsen J, Jakobsen KR, Daugaard TF, et al.
Regulatory dissection of the CBX5 and hnRNPA1 bi-directional promoter in human breast cancer cells reveals novel transcript variants differentially associated with HP1α down-regulation in metastatic cells.
BMC Cancer. 2016; 16:32 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The three members of the human heterochromatin protein 1 (HP1) family of proteins, HP1α, HP1β, and HPγ, are involved in chromatin packing and epigenetic gene regulation. HP1α is encoded from the CBX5 gene and is a suppressor of metastasis. CBX5 is down-regulated at the transcriptional and protein level in metastatic compared to non-metastatic breast cancer. CBX5 shares a bi-directional promoter structure with the hnRNPA1 gene. But whereas CBX5 expression is down-regulated in metastatic cells, hnRNAP1 expression is constant. Here, we address the regulation of CBX5 in human breast cancer.
METHODS: Transient transfection and transposon mediated integration of dual-reporter mini-genes containing the bi-directional hnRNPA1 and CBX5 promoter was performed to investigate transcriptional regulation in breast cancer cell lines. Bioinformatics and functional analysis were performed to characterize transcriptional events specifically regulating CBX5 expression. TSA treatment and Chromatin Immunoprecipitation (ChIP) were performed to investigate the chromatin structure along CBX5 in breast cancer cells. Finally, expression of hnRNPA1 and CBX5 mRNA isoforms were measured by quantitative reverse transcriptase PCR (qRT-PCR) in breast cancer tissue samples.
RESULTS: We demonstrate that an hnRNPA1 and CBX5 bi-directional core promoter fragment does not comprise intrinsic capacity for specific CBX5 down-regulation in metastatic cells. Characterization of transcriptional events in the 20 kb CBX5 intron 1 revealed existence of several novel CBX5 transcripts. Two of these encode consensus HP1α protein but used autonomous promoters in intron 1 by which HP1α expression could be de-coupled from the bi-directional promoter. In addition, another CBX5 transcriptional isoform, STET, was discovered. This transcript includes CBX5 exon 1 and part of intron 1 sequences but lacks inclusion of HP1α encoding exons. Inverse correlation between STET and HP1α coding CBX5 mRNA expression was observed in breast cancer cell lines and tissue samples from breast cancer patients.
CONCLUSION: We find that HP1α is down-regulated in a mechanism involving CBX5 promoter downstream sequences and that regulation through alternative polyadenylation and splicing generates a transcript, STET, with potential importance in carcinogenesis.

Kralovicova J, Knut M, Cross NC, Vorechovsky I
Exon-centric regulation of ATM expression is population-dependent and amenable to antisense modification by pseudoexon targeting.
Sci Rep. 2016; 6:18741 [PubMed] Free Access to Full Article Related Publications
ATM is an important cancer susceptibility gene that encodes a critical apical kinase of the DNA damage response (DDR) pathway. We show that a key nonsense-mediated RNA decay switch exon (NSE) in ATM is repressed by U2AF, PUF60 and hnRNPA1. The NSE activation was haplotype-specific and was most promoted by cytosine at rs609621 in the NSE 3' splice-site (3'ss), which is predominant in high cancer risk populations. NSE levels were deregulated in leukemias and were influenced by the identity of U2AF35 residue 34. We also identify splice-switching oligonucleotides (SSOs) that exploit competition of adjacent pseudoexons to modulate NSE levels. The U2AF-regulated exon usage in the ATM signalling pathway was centred on the MRN/ATM-CHEK2-CDC25-cdc2/cyclin-B axis and preferentially involved transcripts implicated in cancer-associated gene fusions and chromosomal translocations. These results reveal important links between 3'ss control and ATM-dependent responses to double-strand DNA breaks, demonstrate functional plasticity of intronic variants and illustrate versatility of intronic SSOs that target pseudo-3'ss to modify gene expression.

Dao KH, Tyner JW
What's different about atypical CML and chronic neutrophilic leukemia?
Hematology Am Soc Hematol Educ Program. 2015; 2015:264-71 [PubMed] Free Access to Full Article Related Publications
Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare myeloid neoplasms defined largely by morphologic criteria. The discovery of CSF3R mutations in aCML and CNL have prompted a more comprehensive genetic profiling of these disorders. These studies have revealed aCML to be a genetically more heterogeneous disease than CNL, however, several groups have reported that SETBP1 and ASXL1 mutations occur at a high frequency and carry prognostic value in both diseases. We also report a novel finding-our study reveals a high frequency of U2AF1 mutations at codon Q157 associated with CSF3R mutant myeloid neoplasms. Collectively, these findings will refine the WHO diagnostic criteria of aCML and CNL and help us understand the genetic lesions and dysregulated signaling pathways contributing to disease development. Novel therapies that emerge from these genetic findings will need to be investigated in the setting of a clinical trial to determine the safety and efficacy of targeting various oncogenic drivers, such as JAK1/2 inhibition in CSF3R-T618I-positive aCML and CNL. In summary, recent advances in the genetic characterization of CNL and aCML are instrumental toward the development of new lines of therapy for these rare leukemias that lack an established standard of care and are historically associated with a poor prognosis.

Anders QS, Stur E, Agostini LP, et al.
MTHFR C677T and A1298C polymorphisms as predictors of radiotherapy response in head and neck squamous cell carcinoma.
Genet Mol Res. 2015; 14(4):13105-9 [PubMed] Related Publications
The C677T and A1298C polymorphisms in methylene-tetrahydrofolate reductase (MTHFR), which regulates the release of active folate in the body, may have reduced activity. Given that folate participates in important intracellular pathways, such as nucleotide synthesis and biomolecule methylation, it seems plausible that patients with head and neck squamous cell carcinoma (HNSCC) may respond differently to radiotherapy treatments, based on genetic polymor-phisms. Therefore, this study sought to understand the role of these polymorphisms in HNSCC patient radiotherapy response. Genotypes were detected by PCR-RFLP after extraction of DNA from peripheral blood lymphocytes. Survival curves were analyzed by the Kaplan- Meier model, and significant differences were analyzed by the Wil-coxon test. Response to radiotherapy in patients with laryngeal SCC was significantly associated with the MTHFR C677T polymorphism (P = 0.030). Indeed, the presence of at least one T allele decreases the mortality rate up to 3-fold. Therefore, we propose that MTHFR C677T may represent a putative biomarker for radiotherapy prognosis in la-ryngeal SCC patients.

Stur E, Agostini LP, Garcia FM, et al.
Prognostic significance of head and neck squamous cell carcinoma repair gene polymorphism.
Genet Mol Res. 2015; 14(4):12446-54 [PubMed] Related Publications
The aims of this study were to analyze the polymorphisms XRCC1 Arg194Trp, XRCC1 Arg399Gln, XRCC3 Thr241Met, XPC Lys939Gln, ERCC1 Asn118Asn, and RAD51 -98G>C and to verify their influence on radiotherapy response and prognosis of patients with head and neck squamous cell carcinoma (HNSCC). Peripheral blood DNA was extracted from 311 patients and analyzed by PCR-RFLP. Our results showed that in irradiated oral and oropharyngeal patients, the 939Gln allele increased 6-fold local disease relapse risk (OR = 6.04; CI = 1.47-24.88) and over 2-fold the earliness of relapse (HR = 2.63; CI = 1.04-6.70). As for the XRCC3 polymorphism, multivariate analysis showed that the 241Met allele increases over 33-fold local relapse risk (OR = 33.64; CI = 3.23-350.85), over 12-fold earliness of relapse (HR = 12.55; CI = 2.47-63.73) and over 3-fold earliness of death (HR = 3.04; CI = 1.08-8.61). For polymorphism RAD51 -98, multivariate analysis showed that allele C increases over 3-fold the risk of relapse (OR = 3.13; CI = 1.12-8.78) and over 2-fold the earliness of relapse (HR = 2.84; CI = 1.25-6.47). For polymorphism XRCC1 Arg399Gln, multivariate analysis showed that the 399Gln allele increased the risk of local disease relapse for irradiated oral and oropharyngeal patients (OR = 3.35; CI = 1.10-10.13) by over 3-fold. Based on these results, we suggest that these polymorphisms may be useful markers of prognosis in HNSCC.

Jakubauskienė E, Peciuliene I, Vilys L, et al.
Gastrointestinal tract tumors and cell lines possess differential splicing factor expression and tumor associated mRNA isoform formation profiles.
Cancer Biomark. 2015; 15(5):575-81 [PubMed] Related Publications
BACKGROUND: Cell lines derived from human tumors have been extensively used as experimental models of neoplastic disease. Although such cell lines differ from both normal and cancerous tissue.
OBJECTIVE: The data obtained used DNA and RNA microarray systems does not give full information about protein expression levels in cells and tissues. We present experimental evidence that splicing factor SRSF1, SRSF2, U2AF35, U2AF65 and KHSRP expression levels in gastrointestinal tract (colon, gastric and pancreatic) tumors differ compare to healthy tissues and in cell lines, derived from corresponding organs.
METHODS: Protein expression was analyzed using Western blots. RT-PCR method was used for Fas and Rac splicing analysis.
RESULTS: Obtained results provided a novel molecular characterization of this important group of human cell lines and their relationships to tumors in vivo. Expression levels of individual splicing factors in tumors might serve as tumor markers. Not all experimental results obtained from cell lines reflect changes that occur in tumors. Also Fas and Rac, cancer associated genes, tumor associated sFas and Rac1b mRNA isoform profiles in cell lines do not correspond to profiles that are observed in tumors.
CONCLUSIONS: Not all experimental results obtained in cell lines reflect changes that occur in real tumors.

Peterle GT, Santos M, Mendes SO, et al.
FAS ligand expression in inflammatory infiltrate lymphoid cells as a prognostic marker in oral squamous cell carcinoma.
Genet Mol Res. 2015; 14(3):11145-53 [PubMed] Related Publications
Currently, the most important prognostic factor in oral squamous cell carcinoma (OSCC) is the presence of regional lymph node metastases, which correlates with a 50% reduction in life expectancy. We have previously observed that expression of hypoxia genes in the tumor inflammatory infiltrate is statistically related to prognosis in OSCC. FAS and FASL expression levels in OSCC have previously been related to patient survival. The present study analyzed the relationship between FASL expression in the inflammatory infiltrate lymphoid cells and clinical variables, tumor histology, and prognosis of OSCC. Strong FASL expression was significantly associated with lymph node metastases (P = 0.035) and disease-specific death (P = 0.014), but multivariate analysis did not confirm FASL expression as an independent death risk factor (OR = 2.78, 95%CI = 0.81-9.55). Disease-free and disease-specific survival were significantly correlated with FASL expression (P = 0.016 and P = 0.005, respectively). Multivariate analysis revealed that strong FASL expression is an independent marker for earlier disease relapse and disease-specific death, with approximately 2.5-fold increased risk compared with weak expression (HR = 2.24, 95%CI = 1.08-4.65 and HR = 2.49, 95%CI = 1.04-5.99, respectively). Our results suggest a potential role for this expression profile as a tumor prognostic marker in OSCC patients.

Santos M, Maia LL, Silva CV, et al.
DAP1 high expression increases risk of lymph node metastases in squamous cell carcinoma of the oral cavity.
Genet Mol Res. 2015; 14(3):10515-23 [PubMed] Related Publications
Death-associated protein 1 (DAP1) is a member of the DAP family. Its expression is associated with cell growth and normal death of the neoplastic cells, regulated by the mammalian target of the rapamycin protein. Activated DAP1 negatively regulates autophagy, which has been associated with the development and progression of several diseases, such as cancer, and with prognosis and survival of diverse tumor types. Therefore, in this study we analyzed DAP1 expression in 54 oral squamous cell carcinoma tumor samples and in 20 non-tumoral margins by immunohistochemistry. The results showed that DAP1 is more frequently expressed in tumor tissues compared with marginal non-tumoral cells. Additionally, high DAP1 expression is associated with a 4-fold increase in the risk of lymph node metastases. Our results suggest that the DAP1 protein can be used as a potential marker of lymph node metastases predisposition, helping define the best therapy for each patient to minimize risk of developing metastases.

Tefferi A, Lasho TL, Begna KH, et al.
A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.
N Engl J Med. 2015; 373(10):908-19 [PubMed] Related Publications
BACKGROUND: Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.
METHODS: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions.
RESULTS: A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P=0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P=0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P=0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%).
CONCLUSIONS: Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression. (Funded by Geron; ClinicalTrials.gov number, NCT01731951.).

Hsu TY, Simon LM, Neill NJ, et al.
The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
Nature. 2015; 525(7569):384-8 [PubMed] Free Access to Full Article Related Publications
MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

Wan F, Wang H, Shen Y, et al.
Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients.
Oncotarget. 2015; 6(29):27378-87 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The extracellular matrix (ECM) is reported to play an important role in tumorigenesis and progression. Collagen VI is an important ECM protein. In this study, we investigated the potential role of the COL6A1 gene, which encodes the α1 polypeptide of collagen VI, in the biological functions involved in the progression and outcome of clear cell renal cell carcinoma (ccRCC).
MATERIALS AND METHODS: A total of 288 ccRCC patients who underwent radical nephrectomy (RN) or nephron sparing nephrectomy (NSS) at Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Total RNA was extracted from frozen samples obtained from the tissue bank of FUSCC and expression of COL6A1 was determined by qRT-PCR. The clinical relationship between COL6A1 expression and ccRCC prognosis was analyzed. These data were then validated in the Cancer Genome Atlas (TCGA) cohort. We also investigated the effect of COL6A1 overexpression in a xenografted tumor model in nude mice in vivo.
RESULTS: In multivariate analysis of TCGA cohorts, COL6A1 high expression was predictive of poor prognosis in ccRCC patients' overall survival (OS) (HR: 2.588 95%CI 1.616-4.146) and disease free survival(DFS) (HR: 3.106 95%CI 1.534-6.288). In FUSCC cohorts, after adjusted for relevant factors, the COL6A1 expression indicates poor prognosis in ccRCC patients's OS (HR 2.211; 95% CI, 1.360-8.060) and DFS (HR 3.052; 95%CI, 1.500-6.210). COL6A1 overexpression promoted tumor growth in xenografted nude mice.
CONCLUSION: Increased COL6A1 expression correlates with poor prognosis in ccRCC patients. Moreover, COL6A1 stimulates tumor growth in vivo.

Boratyn E, Nowak I, Horwacik I, et al.
Monocyte Chemoattractant Protein-Induced Protein 1 Overexpression Modulates Transcriptome, Including MicroRNA, in Human Neuroblastoma Cells.
J Cell Biochem. 2016; 117(3):694-707 [PubMed] Related Publications
The recently discovered MCPIP1 (monocyte chemoattractant protein-induced protein 1), a multidomain protein encoded by the MCPIP1 (ZC3H12A) gene, has been described as a new differentiation factor, a ribonuclease, and a deubiquitination-supporting factor. However, its role in cancer is poorly recognized. Our recent analysis of microarrays data showed a lack of expression of the MCPIP1 transcript in primary neuroblastoma, the most common extracranial solid tumor in children. Additionally, enforced expression of the MCPIP1 gene in BE(2)-C cells caused a significant decrease in neuroblastoma proliferation and viability. Aim of the present study was to further investigate the role of MCPIP1 in neuroblastoma, using expression DNA microarrays and microRNA microarrays. Transient transfections of BE(2)-C cells were used for overexpression of either wild type of MCPIP1 (MCPIP1-wt) or its RN-ase defective mutant (MCPIP1-ΔPIN). We have analyzed changes of transcriptome and next, we have used qRT-PCR to verify mRNA levels of selected genes responding to MCPIP1 overexpression. Additionally, protein levels were determined for some of the selected genes. The choline transporter, CTL1, encoded by the SLC44A1 gene, was significantly repressed at the specific mRNA and protein levels and most importantly this translated into a decreased choline transport in MCPIP1-overexpressing cells. Then, we have found microRNA-3613-3p as the mostly altered in the pools of cells overexpressing the wild type MCPIP1. Next, we analyzed the predicted targets of the miR-3613-3p and validated them using qRT-PCR and western blot. These results indicate that the expression of miR-3613-3p might be regulated by MCPIP1 by cleavage of its precursor form.

Cheng X, He J, Gan W, et al.
Pseudocapsule of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion: a clue for tumor enucleation?
Int J Clin Exp Pathol. 2015; 8(5):5403-10 [PubMed] Free Access to Full Article Related Publications
OBJECTIVES: To evaluate the feasibility and efficacy of tumor enucleation (TE) for patients with small renal cell carcinoma (RCC) associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 RCC) by analyzing the pseudocapsule characteristics of Xp11.2 RCCs comparing with that of clear cell renal cell carcinoma (ccRCC).
METHODS: From June 2007 to February 2014, 22 patients with Xp11.2 RCC who were diagnosed by fluorescence in-situ hybridization polyclonal (FISH) assay and 32 patients with ccRCC treated in our institution were comparatively studied. 12 patients with ccRCC underwent radical nephrectomy (RN) and 20 received TE. Among 22 patients with Xp11.2 RCC, 19 were treated by RN and 3 by TE (1 by radiofrequency ablation assisted TE). Pseudocapsule and other clinicopathological characteristics of the two subtypes of RCC were compared. Survival of patients treated with different surgical methods was evaluated and compared.
RESULTS: Pseudocapsule incidence of Xp11.2 RCC (14/22, 63.6%) was lower than that of ccRCC (32/32, 100%, P<0.001). However, pseudocapsule integrity rate of Xp11.2 RCC (10/14, 71.4%) was comparable with that of ccRCC (23/32, 71.9%, P=1.000). The 5-year overall survival of patients with ccRCC treated with RN and TE was 86% and 81%, respectively (P=0.845). Three patients with small Xp11.2 RCC performed well after TE.
CONCLUSIONS: Over half Xp11.2 RCC had pseudocapsules, whose integrity rate was comparable to that of ccRCC. Treatment effectives of TE and RN were comparable in ccRCC. A preliminary attempt to treat small Xp11.2 RCC with intact pseudocapsule by using TE produced a favorable treatment outcome.

Kang MG, Kim HR, Seo BY, et al.
The prognostic impact of mutations in spliceosomal genes for myelodysplastic syndrome patients without ring sideroblasts.
BMC Cancer. 2015; 15:484 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mutations in genes that are part of the splicing machinery for myelodysplastic syndromes (MDS), including MDS without ring sideroblasts (RS), have been widely investigated. The effects of these mutations on clinical outcomes have been diverse and contrasting.
METHODS: We examined a cohort of 129 de novo MDS patients, who did not harbor RS, for mutations affecting three spliceosomal genes (SF3B1, U2AF1, and SRSF2).
RESULTS: The mutation rates of SF3B1, U2AF1, and SRSF2 were 7.0 %, 7.8 %, and 10.1 %, respectively. Compared with previously reported results, these rates were relatively infrequent. The SRSF2 mutation strongly correlated with old age (P < 0.001), while the mutation status of SF3B1 did not affect overall survival (OS), progression-free survival (PFS), or acute myeloid leukemia (AML) transformation. In contrast, MDS patients with mutations in U2AF1 or SRSF2 exhibited inferior PFS. The U2AF1 mutation was associated with inferior OS in low-risk MDS patients (P = 0.035). The SRSF2 mutation was somewhat associated with AML transformation (P = 0.083).
CONCLUSION: Our findings suggest that the frequencies of the SF3B1, U2AF1, and SRSF2 splicing gene mutations in MDS without RS were relatively low. We also demonstrated that the U2AF1 and SRSF2 mutations were associated with an unfavorable prognostic impact in MDS patients without RS.

Lajus TB, Sales RM
CDH1 germ-line missense mutation identified by multigene sequencing in a family with no history of diffuse gastric cancer.
Gene. 2015; 568(2):215-9 [PubMed] Related Publications
Germ-line mutation in CDH1 gene is associated with high risk for Hereditary Diffuse Gastric Cancer (HDGC) and Infiltrative Lobular Carcinoma (ILC). Although somatic CDH1 mutations were also detected in ILC with a frequency ranging from 10 to 56%, CDH1 alterations in more frequent infiltrative ductal carcinoma (IDC) appear to be rare, and no association with germ-line CDH1 mutation and IDC has been established. Here we report the case of a woman diagnosed with IDC at 39years of age, presenting extensive familial history of cancer at multiple sites with early-age onset and with no case of HDGC. Deep sequencing have revealed CDH1 missense mutation c.1849G>A (p.Ala617Thr) in heterozygous and four BRCA2 single nucleotide polymorphism in homozygosis. In this family, the mutation c.1849G>A in the CDH1 gene is not related to HDGC nor ILC. Therefore, here we highlight that multigene analysis is important to detect germ-line mutations and genetic variants in patients with cancers at multiple sites in the family, even if inconclusive genetic counseling can be offered, since hereafter, medical awareness will be held.

Gioia R, Trégoat C, Dumas PY, et al.
CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.
J Pathol. 2015; 237(1):14-24 [PubMed] Related Publications
A tyrosine kinase network composed of the TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib-resistance of chronic myeloid leukaemia (CML) cells. Here, we show that the E3-ubiquitin ligase CBL down-regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL in K562 cells increases AXL and LYN protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL in nilotinib-resistant K562 cells (K562-rn) dramatically reduces AXL and LYN expression and resensitizes K562-rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34(+) cells. Mechanistically, the E3-ligase CBL counteracts AXL/SYK signalling, promoting LYN transcription by controlling AXL protein stability. Surprisingly, the role of AXL in resistance was independent of its ligand GAS6 binding and its TK activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML cells.

Shirai CL, Ley JN, White BS, et al.
Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo.
Cancer Cell. 2015; 27(5):631-43 [PubMed] Free Access to Full Article Related Publications
Heterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼ 11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.

Blein S, Bardel C, Danjean V, et al.
An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.
Breast Cancer Res. 2015; 17:61 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.
RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.
CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Falgreen S, Dybkær K, Young KH, et al.
Predicting response to multidrug regimens in cancer patients using cell line experiments and regularised regression models.
BMC Cancer. 2015; 15:235 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Patients suffering from cancer are often treated with a range of chemotherapeutic agents, but the treatment efficacy varies greatly between patients. Based on recent popularisation of regularised regression models the goal of this study was to establish workflows for pharmacogenomic predictors of response to standard multidrug regimens using baseline gene expression data and origin specific cell lines. The proposed workflows are tested on diffuse large B-cell lymphoma treated with R-CHOP first-line therapy.
METHODS: First, B-cell cancer cell lines were tested successively for resistance towards the chemotherapeutic components of R-CHOP: cyclophosphamide (C), doxorubicin (H), and vincristine (O). Second, baseline gene expression data were obtained for each cell line before treatment. Third, regularised multivariate regression models with cross-validated tuning parameters were used to generate classifier and predictor based resistance gene signatures (REGS) for the combination and individual chemotherapeutic drugs C, H, and O. Fourth, each developed REGS was used to assign resistance levels to individual patients in three clinical cohorts.
RESULTS: Both classifier and predictor based REGS, for the combination CHO, were of prognostic value. For patients classified as resistant towards CHO the risk of progression was 2.33 (95% CI: 1.6, 3.3) times greater than for those classified as sensitive. Similarly, an increase in the predicted CHO resistance index of 10 was related to a 22% (9%, 36%) increased risk of progression. Furthermore, the REGS classifier performed significantly better than the REGS predictor.
CONCLUSIONS: The regularised multivariate regression models provide a flexible workflow for drug resistance studies with promising potential. However, the gene expressions defining the REGSs should be functionally validated and correlated to known biomarkers to improve understanding of molecular mechanisms of drug resistance.

Dybkær K, Bøgsted M, Falgreen S, et al.
Diffuse large B-cell lymphoma classification system that associates normal B-cell subset phenotypes with prognosis.
J Clin Oncol. 2015; 33(12):1379-88 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Current diagnostic tests for diffuse large B-cell lymphoma use the updated WHO criteria based on biologic, morphologic, and clinical heterogeneity. We propose a refined classification system based on subset-specific B-cell-associated gene signatures (BAGS) in the normal B-cell hierarchy, hypothesizing that it can provide new biologic insight and diagnostic and prognostic value.
PATIENTS AND METHODS: We combined fluorescence-activated cell sorting, gene expression profiling, and statistical modeling to generate BAGS for naive, centrocyte, centroblast, memory, and plasmablast B cells from normal human tonsils. The impact of BAGS-assigned subtyping was analyzed using five clinical cohorts (treated with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], n = 270; treated with rituximab plus CHOP [R-CHOP], n = 869) gathered across geographic regions, time eras, and sampling methods. The analysis estimated subtype frequencies and drug-specific resistance and included a prognostic meta-analysis of patients treated with first-line R-CHOP therapy.
RESULTS: Similar BAGS subtype frequencies were assigned across 1,139 samples from five different cohorts. Among R-CHOP-treated patients, BAGS assignment was significantly associated with overall survival and progression-free survival within the germinal center B-cell-like subclass; the centrocyte subtype had a superior prognosis compared with the centroblast subtype. In agreement with the observed therapeutic outcome, centrocyte subtypes were estimated as being less resistant than the centroblast subtype to doxorubicin and vincristine. The centroblast subtype had a complex genotype, whereas the centrocyte subtype had high TP53 mutation and insertion/deletion frequencies and expressed LMO2, CD58, and stromal-1-signature and major histocompatibility complex class II-signature genes, which are known to have a positive impact on prognosis.
CONCLUSION: Further development of a diagnostic platform using BAGS-assigned subtypes may allow pathogenetic studies to improve disease management.

Fernandes JV, Cobucci RN, Jatobá CA, et al.
The role of the mediators of inflammation in cancer development.
Pathol Oncol Res. 2015; 21(3):527-34 [PubMed] Related Publications
Epigenetic disorders such as point mutations in cellular tumor suppressor genes, DNA methylation and post-translational modifications are needed to transformation of normal cells into cancer cells. These events result in alterations in critical pathways responsible for maintaining the normal cellular homeostasis, triggering to an inflammatory response which can lead the development of cancer. The inflammatory response is a universal defense mechanism activated in response to an injury tissue, of any nature, that involves both innate and adaptive immune responses, through the collective action of a variety of soluble mediators. Many inflammatory signaling pathways are activated in several types of cancer, linking chronic inflammation to tumorigenesis process. Thus, Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, growth, invasion, and metastasis, affecting also the immune surveillance. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. A range of inflammation mediators, including cytokines, chemokines, free radicals, prostaglandins, growth and transcription factors, microRNAs, and enzymes as, cyclooxygenase and matrix metalloproteinase, collectively acts to create a favorable microenvironment for the development of tumors. In this review are presented the main mediators of the inflammatory response and discussed the likely mechanisms through which, they interact with each other to create a condition favorable to development of cancer.

Patnaik MM, Wassie EA, Lasho TL, et al.
Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome.
Am J Hematol. 2015; 90(5):411-6 [PubMed] Related Publications
Among 274 patients with chronic myelomonocytic leukemia (CMML) and followed for a median of 17.1 months, blast transformation (BT) occurred in 36 (13%). On multivariable analysis, risk factors for BT were presence of circulating blasts (HR 5.7; 95% CI 2.8-11.9) and female gender (HR 2.6; 95% CI 1.3-5.1); the results remained unchanged when analysis was restricted to CMML-1. ASXL1/SRSF2/SF3B1/U2AF1/SETBP1 mutational frequencies were not significantly different between time of CMML diagnosis and BT. Median survival post-BT was 4.7 months (5-year survival 6%) and better with allogeneic stem cell transplant (SCT) (14.3 months vs. 4.3 months for chemotherapy vs. 0.9 months for supportive care; P = 0.03). Neither karyotype nor mutational status was independently associated with risk of BT or post-BT survival. We conclude that female patients with CMML and those with circulating blasts are at a higher risk of BT. Post-BT survival is dismal and our observations suggest consideration of allogeneic SCT prior to BT.

Choi HW, Kim HR, Baek HJ, et al.
Alteration of the SETBP1 gene and splicing pathway genes SF3B1, U2AF1, and SRSF2 in childhood acute myeloid leukemia.
Ann Lab Med. 2015; 35(1):118-22 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recurrent somatic SET-binding protein 1 (SETBP1) and splicing pathway gene mutations have recently been found in atypical chronic myeloid leukemia and other hematologic malignancies. These mutations have been comprehensively analyzed in adult AML, but not in childhood AML. We investigated possible alteration of the SETBP1, splicing factor 3B subunit 1 (SF3B1), U2 small nuclear RNA auxiliary factor 1 (U2AF1), and serine/arginine-rich splicing factor 2 (SRSF2) genes in childhood AML.
METHODS: Cytogenetic and molecular analyses were performed to reveal chromosomal and genetic alterations. Sequence alterations in the SETBP1, SF3B1, U2AF1, and SRSF2 genes were examined by using direct sequencing in a cohort of 53 childhood AML patients.
RESULTS: Childhood AML patients did not harbor any recurrent SETBP1 gene mutations, although our study did identify a synonymous mutation in one patient. None of the previously reported aberrations in the mutational hotspot of SF3B1, U2AF1, and SRSF2 were identified in any of the 53 patients.
CONCLUSIONS: Alterations of the SETBP1 gene or SF3B1, U2AF1, and SRSF2 genes are not common genetic events in childhood AML, implying that the mutations are unlikely to exert a driver effect in myeloid leukemogenesis during childhood.

Hahn CN, Venugopal P, Scott HS, Hiwase DK
Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy.
Immunol Rev. 2015; 263(1):257-78 [PubMed] Related Publications
Differential splicing contributes to the vast complexity of mRNA transcripts and protein isoforms that are necessary for cellular homeostasis and response to developmental cues and external signals. The hematopoietic system provides an exquisite example of this. Recently, discovery of mutations in components of the spliceosome in various hematopoietic malignancies (HMs) has led to an explosion in knowledge of the role of splicing and splice factors in HMs and other cancers. A better understanding of the mechanisms by which alternative splicing and aberrant splicing contributes to the leukemogenic process will enable more efficacious targeted approaches to tackle these often difficult to treat diseases. The clinical implications are only just starting to be realized with novel drug targets and therapeutic strategies open to exploitation for patient benefit.

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