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N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.
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Adenosina/química , Hematopoyesis/genética , Hematopoyesis/inmunología , Inmunidad Innata/genética , ARN Bicatenario/metabolismo , Animales , Biomarcadores , Trastornos de Fallo de la Médula Ósea/etiología , Trastornos de Fallo de la Médula Ósea/metabolismo , Trastornos de Fallo de la Médula Ósea/patología , Diferenciación Celular/genética , Modelos Animales de Enfermedad , Epigénesis Genética , Expresión Génica , Células Madre Hematopoyéticas , Inmunofenotipificación , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Ratones Noqueados , ARN Bicatenario/químicaRESUMEN
OBJECTIVES: Despite a high risk of human papillomavirus (HPV) infection among men who have sex with men (MSM), few have ever tested. This study aimed to evaluate the feasibility and accuracy of HPV self-sampling among Chinese MSM, with the purpose of measuring the feasibility of self-sampling as an alternative in HPV testing scenarios. METHODS: Eligible participants were those who were assigned male at birth, aged 18 or above, had sex with men in the past year and had never gotten HPV vaccine. Participants followed the instructions to self-sample and were also clinician-sampled from the same anatomical sites (oral fluid, penis and rectum) in both approaches. All specimens were processed using multiplex PCR assay. The reference standard of an individual with a true positive for HPV is determined via PCR test, regardless of sampling methods. Sensitivity and specificity were calculated for each approach independently and kappa test was used to assess the consistency between the two approaches. RESULTS: Overall, 211 MSM were recruited at the local clinic from April to October 2020 in Zhuhai, China. The mean age was 31 years old. Only 3% of the participants sought help from healthcare providers during self-sampling. The prevalence of HPV was 49% (103 of 211). Clinician sampling detected 91 of 103 MSM infected with HPV, with a sensitivity of 88.3% (95% CI 80.2 to 93.6) and a specificity of 100.0% (95% CI 95.7 to 100.0). Self-sampling detected 81 of 103 MSM infected with HPV, with a sensitivity of 78.6% (95% CI 69.2 to 85.9) and a specificity of 100.0% (95% CI 95.7 to 100.0). The level of agreement was moderate between clinician sampling and self-sampling (k=0.67). CONCLUSIONS: Self-sampled HPV testing demonstrated comparable accuracy and consistency to clinician sampling among MSM in China. It holds the potential to complement sexual health services especially among key populations.
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Infecciones por Papillomavirus , Minorías Sexuales y de Género , Recién Nacido , Humanos , Masculino , Adulto , Homosexualidad Masculina , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Manejo de Especímenes/métodos , Pene , Papillomaviridae/genéticaRESUMEN
Persistent infections of high-risk human papillomaviruses (HPVs) are the leading cause of cervical cancers. We collected cervical exfoliated cell samples from females in Changsha city, Hunan Province and obtained 338 viral genomes of four major HPV types, including HPV 16 (n = 82), 18 (n = 35), 52 (n = 121) and 58 (n = 100). The lineage/sublineage distribution of the four HPVs confirmed previous epidemiological reports, with the predominant prevailing sublineage as A4 (50%), A1 (37%) and A3 (13%) for HPV16, A1 (83%) for HPV18, B2 (86%) for HPV52 and A1 (65%), A3 (19%) and A2 (12%) for HPV58. We also identified two potentially novel HPV18 sublineages, i.e. A6 and A7. Virus mutation analysis further revealed the presence of HPV16 and HPV58 sublineages associated with potentially high oncogenicity. These findings expanded our knowledge of the HPV genetic diversity in China, providing valuable evidence to facilitate HPV DNA screening, vaccine effectiveness evaluation and control strategy development.
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Alphapapillomavirus , Infecciones por Papillomavirus , Alphapapillomavirus/genética , China/epidemiología , Femenino , Variación Genética , Genotipo , Papillomavirus Humano 16/genética , Humanos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , FilogeniaRESUMEN
Metabolism reprogramming is one of the hallmarks of cancer cells, especially glucose metabolism, to promote their proliferation, metastasis and drug resistance. Cancer cells tend to depend on glycolysis for glucose utilization rather than oxidative phosphorylation, which is called the Warburg effect. Genome instability of oncogenes and tumor-inhibiting factors is the culprits for this anomalous glycolytic fueling, which results in dysregulating metabolism-related enzymes and metabolic signaling pathways. It has been extensively demonstrated that protein-coding genes are involved in this process; therefore, glycolysis-targeted therapy has been widely used in anti-tumor combined therapy via small molecular inhibitors of key enzymes and regulatory molecular. The long non-coding RNA, which is a large class of regulatory RNA with longer than 200 nucleotides, is the novel and significant regulator of various biological processes, including metabolic reprogramming. RNA interference and synthetic antisense oligonucleotide for RNA reduction have developed rapidly these years, which presents potent anti-tumor effects both in vitro and in vivo. However, lncRNA-based glycolysis-targeted cancer therapy, as the highly specific and less toxic approach, is still under the preclinical phase. In this review, we highlight the role of lncRNA in glucose metabolism and dissect the feasibility and limitations of this clinical development, which may provide potential targets for cancer therapy.
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Glucólisis/genética , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , ARN Largo no Codificante/metabolismo , Ensayos Clínicos como Asunto , Estudios de Factibilidad , Humanos , ARN Largo no Codificante/genéticaRESUMEN
Numerous studies confirmed that aberrant microRNA (miRNA) expression contributes to cancer development and progression. We carried out this study to explore the expression profile of miRNAs in intermediate risk acute myeloid leukemia (AML) and locate certain miRNAs as biomarkers. We profiled differentially expressed miRNAs by performing miRNA sequencing analysis in the patients' samples. Bioinformatic analysis showed the most significantly expressed genes mostly involved in cellular component organization, cell differentiation, and cell development. Reverse-transcription polymerase chain reaction validated the expression of miR-582-5p in different groups of AML samples. It was confirmed that miR-582-5p was downregulated in newly diagnosed AML and relapse/refractory AML compared with CR AML or controls. Among intermediate risk AML patients with normal cytogenetics, a lower level of miR-582-5p is correlated with an unfavorable outcome, and a shorter overall survival. Gain- and loss-of-function experiments revealed that miR-582-5p could inhibit proliferation, suppress migration, and invasion ability and induce apoptosis of leukemia cells. Furthermore, overexpression of miR-582-5p can increase sensitivity of cells to Ara-C. In conclusion, miR-582-5p can serve as an antioncogenic biomarker in intermediate risk AML with normal cytogenetics for risk classification and outcome prediction. These results showed a novel role for miR-582-5p in predicting the prognosis and promoting the tumor growth of AML.
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Biomarcadores de Tumor/metabolismo , Médula Ósea , Leucemia Mieloide Aguda , MicroARNs/metabolismo , Adulto , Apoptosis , Médula Ósea/metabolismo , Médula Ósea/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
BACKGROUND: Massively-parallel-sequencing, coupled with sample multiplexing, has made genetic tests broadly affordable. However, intractable index mis-assignments (commonly exceeds 1%) were repeatedly reported on some widely used sequencing platforms. RESULTS: Here, we investigated this quality issue on BGI sequencers using three library preparation methods: whole genome sequencing (WGS) with PCR, PCR-free WGS, and two-step targeted PCR. BGI's sequencers utilize a unique DNA nanoball (DNB) technology which uses rolling circle replication for DNA-nanoball preparation; this linear amplification is PCR free and can avoid error accumulation. We demonstrated that single index mis-assignment from free indexed oligos occurs at a rate of one in 36 million reads, suggesting virtually no index hopping during DNB creation and arraying. Furthermore, the DNB-based NGS libraries have achieved an unprecedentedly low sample-to-sample mis-assignment rate of 0.0001 to 0.0004% under recommended procedures. CONCLUSIONS: Single indexing with DNB technology provides a simple but effective method for sensitive genetic assays with large sample numbers.
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Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Bacterias/genética , Humanos , Secuenciación Completa del Genoma , Flujo de TrabajoRESUMEN
PURPOSE: The benefits of concurrent newborn hearing and genetic screening have not been statistically proven due to limited sample sizes and outcome data. To fill this gap, we analyzed outcomes of newborns with genetic screening results. METHODS: Newborns in China were screened for 20 hearing-loss-related genetic variants from 2012 to 2017. Genetic results were categorized as positive, at-risk, inconclusive, or negative. Hearing screening results, risk factors, and up-to-date hearing status were followed up via phone interviews. RESULTS: Following up 12,778 of 1.2 million genetically screened newborns revealed a higher rate of hearing loss by three months of age among referrals from the initial hearing screening (60% vs. 5.0%, P < 0.001) and a lower rate of lost-to-follow-up/documentation (5% vs. 22%, P < 0.001) in the positive group than in the inconclusive group. Importantly, genetic screening detected 13% more hearing-impaired infants than hearing screening alone and identified 2,638 (0.23% of total) newborns predisposed to preventable ototoxicity undetectable by hearing screening. CONCLUSION: Incorporating genetic screening improves the effectiveness of newborn hearing screening programs by elucidating etiologies, discerning high-risk subgroups for vigilant management, identifying additional children who may benefit from early intervention, and informing at-risk newborns and their maternal relatives of increased susceptibility to ototoxicity.
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Pruebas Genéticas/métodos , Pérdida Auditiva/genética , Tamizaje Neonatal/métodos , China/epidemiología , Sordera/genética , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/tendencias , Genética de Población , Pérdida Auditiva Sensorineural/diagnóstico , Pruebas Auditivas , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal/tendenciasRESUMEN
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nt that are involved in tumorigenesis and play a key role in cancer progression. To determine whether lncRNAs are involved in acute myeloid leukemia (AML), we analyzed the expression profile of lncRNAs and mRNAs in AML. Five pairs of AML patients and iron deficiency anemia (IDA) controls were screened by microarray. Through coexpression analysis, differently expressed transcripts were divided into modules, and lncRNAs were functionally annotated. We further analyzed the clinical significance of crucial lncRNAs from modules in public data. Finally, the expression of three lncRNAs, RP11-222K16.2, AC092580.4, and RP11-305O.6, were validated in newly diagnosed AML, AML relapse, and IDA patient groups by quantitative RT-PCR, which may be associated with AML patients' overall survival. Further analysis showed that RP11-222K16.2 might affect the differentiation of natural killer cells, and promote the immunized evasion of AML by regulating Eomesodermin expression. Analysis of this study revealed that dysregulated lncRNAs and mRNAs in AML vs IDA controls could affect the immune system and hematopoietic cell differentiation. The biological functions of those lncRNAs need to be further validated.
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Anemia Ferropénica/genética , Leucemia Mieloide Aguda/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN Largo no Codificante/genética , Estudios de Casos y Controles , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Masculino , Pronóstico , Mapas de Interacción de Proteínas , Análisis de SupervivenciaRESUMEN
BACKGROUND/AIMS: Circular RNAs (circRNAs) are a family of novel non-coding RNAs associated with various diseases, especially cancer. Recent studies have demonstrated that circRNAs participate in pathogenesis mainly by acting as microRNA (miRNA) sponges. The expression profile of circRNAs in acute myeloid leukemia (AML) has rarely been reported. METHODS: Profiles of circRNAs were analyzed using an Arraystar human circRNA microarray with 5 bone marrow samples from patients with newly diagnosed AML and 5 from patients with iron-deficiency anemia. Quantitative reverse transcription PCR was used to validate the expression pattern of circRNAs. Furthermore, circRNA-miRNA network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied. RESULTS: CircRNA microarray analysis revealed that 698 circRNAs were differentially expressed in AML patients, with 282 circRNAs found to be upregulated and 416 to be downregulated. Quantitative reverse transcription PCR showed that circ-ANAPC7 was significantly upregulated in AML. Bioinformatics analysis predicted that circ-ANAPC7 acts as a sponge for the miR-181 family, KEGG analysis revealed that it is associated with cancer-related pathways, and GO analysis indicated that most of its target genes are involved in biological processes. CONCLUSIONS: These findings show that circ-ANAPC7 is a promising biomarker for AML, and that it might participate in AML pathogenesis by acting as a sponge for the miR-181 family.
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Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/metabolismo , MicroARNs/biosíntesis , ARN Neoplásico/biosíntesis , Regulación hacia Arriba , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , MicroARNs/genética , ARN Neoplásico/genéticaRESUMEN
A new type of RNAs was identified from genes traditionally thought to express messenger or linear ncRNA (noncoding RNA) only. They were subsequently named as circRNAs (circular RNAs) due to the covalently closed structure. Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions. The expression profile of circRNAs is tissue-specific and alters across various stages of cell differentiation. The biological function of circRNAs is multi-faceted, involving five main features (sponge effect, post-transcriptional regulation, rolling circle translation, circRNA-derived pseudogenes and splicing interference) and varying differently from the locations, binding sites and acting modes of circRNAs. The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. Although most of the potential functions still remain unclear, circRNAs have been proved to be ubiquitous and critical in regulating cellular processes and diseases, especially in cancers, from the laboratory to the clinic. Herein, we review circRNAs' classification, biogenesis and metabolism, their well-studied and anticipated functions, the current understanding of the potential implications of circRNAs in tumorigenesis and cancer targeted therapy.
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ARN no Traducido/genética , ARN/genética , Animales , Evolución Molecular , Regulación de la Expresión Génica , Humanos , ARN/metabolismo , ARN Circular , ARN no Traducido/metabolismoRESUMEN
MicroRNAs (miRNAs) are a general class of endogenous non-coding RNAs with a length of 22 nucleotides, widely existing in diverse species and playing important roles in malignancies initiation and progression. MiRNAs are essential to many in vivo biological processes such as cell proliferation, apoptosis, immune response, and tumorigenesis. Significant progress till date has been made in understanding the roles of microRNAs in normal hematopoiesis and hematopoietic malignant diseases. In this review, we summarize the particular signatures of microRNAs in acute myeloid leukemia (AML) patients with specific karyotype and the clinical significance of microRNAs in early diagnosis and treatment. MicroRNAs hypermethylation was also proved to correlate with the pathogenesis of AML. However, the target genes and exact pathways of microRNAs participating in these processes are still unknown and more efforts need to be made in the near future.
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Transformación Celular Neoplásica , Perfilación de la Expresión Génica/métodos , Regulación Leucémica de la Expresión Génica , Humanos , Metilación , Procesamiento Postranscripcional del ARNRESUMEN
PURPOSE: Chimeric antigen receptor T-cell (CAR-T) therapy has been proven very effective in treating hematologic malignancies. Ciltacabtagene autoleucel (cilta-cel), a second-generation CAR-T cell with double B cell maturation antigen (BCMA) targeting binding domains, showed an 88% overall response rate (ORR) in patients with relapsed/refractory multiple myeloma (MM), which were carried out in our institute. This study aimed to assess the prognostic potential of soluble BCMA (sBCMA) in serum as a biomarker in MM after CAR-T therapy. PATIENTS AND METHODS: Serum samples (n = 44) from MM patients were collected before and after CAR-T therapy. The level of sBCMA was analyzed by enzyme-linked immunosorbent assay (ELISA). Additionally, three patients' long-term longitudinal analysis were performed. RESULTS: Serum sBCMA level was correlated with the percentage of malignant plasma cells in bone marrow (r = 0.613). After CAR-T infusion, the sBCMA level in serum of MM patients decreased markedly (median: 508,513 pg/mL before CAR-T infusion, 89,198 pg/mL in the first month, 8448 pg/mL in the second months, and 6010 pg/mL in the third month after CAR-T infusion). In patients who obtained objective response (≥ PR), re-elevated sBCMA indicated the possibility of disease recurrence. At a cutoff 69,326.27 pg/mL, sBCMA shows high sensitivity (87.5%) and specificity (88.5%) for identifying relapse of MM after CAR-T therapy. CONCLUSION: Our results suggested that serum sBCMA level changes in response to the clinical status of MM patients after anti-BCMA CAR-T therapy. Furthermore, sBCMA may be a auxiliary biomarker for disease monitoring in MM patients after CAR-T therapy.
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Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Receptores Quiméricos de Antígenos/metabolismo , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/terapia , Recurrencia Local de Neoplasia/etiología , Inmunoterapia Adoptiva/métodos , Linfocitos T/metabolismoRESUMEN
[This corrects the article DOI: 10.7150/ijbs.45999.].
RESUMEN
Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Inhibidores Enzimáticos/farmacología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , RecurrenciaRESUMEN
BACKGROUND: N6-methyladenosine is the most abundant RNA modification, which plays a prominent role in various biology processes, including tumorigenesis and immune regulation. Multiple myeloma (MM) is the second most frequent hematological malignancy. MATERIALS AND METHODS: Twenty-two m6A RNA methylation regulators were analyzed between MM patients and normal samples. Kaplan-Meier survival analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis were employed to construct the risk signature model. Receiver operation characteristic (ROC) curves were used to verify the prognostic and diagnostic efficiency. Immune infiltration level was evaluated by ESTIMATE algorithm and immune-related single-sample gene set enrichment analysis (ssGSEA). RESULTS: High expression of HNRNPC, HNRNPA2B1, and YTHDF2 and low expression of ZC3H13 were associated with poor survival. Based on these four genes, a prognostic risk signature model was established. Multivariate Cox regression analysis demonstrated that the risk score was an independent prognostic factor of MM. Enrichment analysis showed that cell cycle, immune response, MYC, proteasome, and unfold protein reaction were enriched in high-risk MM patients. Furthermore, patients with higher risk score exhibited lower immune scores and lower immune infiltration level. CONCLUSION: The m6A-based prognostic risk score accurately and robustly predicts the survival of MM patients and is associated with the immune infiltration level, which complements current prediction models and enhances our cognition of immune infiltration.
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Increasing evidences indicate that high-risk HPV variants are heterogeneous in carcinogenicity and ethnic dispersion. In this work, we identified genetic signatures for convenient determination of lineage/sublineage of HPV16, 18, 52 and 58 variants. Using publicly available genomes, we found that E2 of HPV16, L2 of HPV18, L1 and LCR of HPV52, and L2, LCR and E1 of HPV58 contain the proper genetic signature for lineage/sublineage classification. Sets of hierarchical signature nucleotide positions were further confirmed for high accuracy (>95%) by classifying HPV genomes obtained from Chinese females, which included 117 HPV16 variants, 48 HPV18 variants, 117 HPV52 variants and 89 HPV58 variants. The circulation of HPV variants posing higher cancer risk in Eastern China, such as HPV16 A4 and HPV58 A3, calls for continuous surveillance in this region. The marker genes and signature nucleotide positions may facilitate cost-effective diagnostic detections of HPV variants in clinical settings.
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Alphapapillomavirus/genética , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Infecciones por Papillomavirus/virología , Alphapapillomavirus/clasificación , Alphapapillomavirus/aislamiento & purificación , China , Femenino , Variación Genética , Genoma Viral , Papillomavirus Humano 16/clasificación , Papillomavirus Humano 16/aislamiento & purificación , Papillomavirus Humano 18/clasificación , Papillomavirus Humano 18/aislamiento & purificación , Humanos , Nucleótidos , Filogenia , Secuenciación Completa del GenomaRESUMEN
In vivo models that recapitulate human erythropoiesis with persistence of circulating red blood cells (RBCs) have remained elusive. We report an immunodeficient murine model in which combined human liver and cytokine humanization confer enhanced human erythropoiesis and RBC survival in the circulation. We deleted the fumarylacetoacetate hydrolase (Fah) gene in MISTRG mice expressing several human cytokines in place of their murine counterparts. Liver humanization by intrasplenic injection of human hepatocytes (huHep) eliminated murine complement C3 and reduced murine Kupffer cell density. Engraftment of human sickle cell disease (SCD)-derived hematopoietic stem cells in huHepMISTRGFah -/- mice resulted in vaso-occlusion that replicated acute SCD pathology. Combined liver-cytokine-humanized mice will facilitate the study of diseases afflicting RBCs, including bone marrow failure, hemoglobinopathies, and malaria, and also preclinical testing of therapies.
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Anemia de Células Falciformes/sangre , Circulación Sanguínea , Modelos Animales de Enfermedad , Eritrocitos/citología , Eritropoyesis/fisiología , Ratones , Animales , Citocinas/metabolismo , Eritropoyesis/genética , Femenino , Eliminación de Gen , Células Madre Hematopoyéticas/citología , Humanos , Hidrolasas/genética , Hígado/fisiología , Ratones Mutantes , Persona de Mediana EdadRESUMEN
AIMS: To investigate the role and mechanism of insulin-like growth factor 1(IGF-1)-mediated EMT on multiple myeloma (MM) growth and metastasis. MATERIALS AND METHODS: The expression data from GEO datasets were utilized to explore the expression levels of IGF-1 and epithelial-mesenchymal transition (EMT) markers in MM. Western blotting and flow cytometry analysis were performed to detect the protein levels of EMT markers as well as key components of the PI3K/Akt pathway. Cell proliferation ability was assessed using colony formation assay and EdU incorporation assays. Transwell migration and invasion assays were performed to assess cell metastasis properties. Vimentin was knocked down by using electro-transfection with small interfering RNA (siRNA) to detect the effect of IGF-1-mediated EMT on MM cell growth and metastasis. KEY FINDINGS: First of all, the analysis of GEO database revealed that IGF-1 was excessively expressed and closely correlated with the expression of the EMT markers in MM patients. Furthermore, we demonstrated that IGF-1 enhanced the acquisition of mesenchymal features in a time-dependent manner. Additionally, in vitro studies revealed that IGF-1-mediated mesenchymal phenotype promoted MM migration, invasion and colony formation. Finally, the mechanism study showed PI3K/Akt signaling pathway was involved in the IGF-1-induced EMT in MM cells. SIGNIFICANCE: IGF-1-induced mesenchymal phenotype contributed to MM progression via the PI3K/Akt pathway regulation.
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Transición Epitelial-Mesenquimal/fisiología , Factor I del Crecimiento Similar a la Insulina/fisiología , Mieloma Múltiple/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Biomarcadores/metabolismo , Línea Celular Tumoral , Proliferación Celular/fisiología , Progresión de la Enfermedad , Regulación hacia Abajo , Humanos , Mieloma Múltiple/metabolismo , Metástasis de la Neoplasia , Transducción de Señal , Regulación hacia Arriba , Vimentina/metabolismoRESUMEN
Krüppel-like factor 10 (KLF10) has been identified as an important regulator in carcinogenesis and cancer progression. However, the role of KLF10 in multiply myeloma (MM) development and progression remains unknown. In present study, we found that KLF10 mRNA and protein were down-regulated in MM tissues and cell lines. Notably, KLF10 inhibited cell proliferation, cell cycle progression and promoted apoptosis in vitro and in vivo. Furthermore, we confirmed that KLF10 inhibited ß-catenin nuclear translocation and inhibited PTTG1 transcription. PTTG1 knockdown could mimic the biological effects of KLF10. Moreover, we demonstrated that KLF10 expression was regulated by miR-106b-5p. In MM tissues, miR-106b-5p has an inverse correlation with KLF10 expression. Conclusively, our results demonstrated that KLF10 functions as a tumor suppressor in regulating tumor growth of MM under regulation of miR-106b-5p, supporting its potential therapeutic target for MM.
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Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , MicroARNs/metabolismo , Mieloma Múltiple/metabolismo , Securina/metabolismo , Animales , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Factores de Transcripción de la Respuesta de Crecimiento Precoz/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Ratones , Ratones Desnudos , MicroARNs/genética , Mieloma Múltiple/genética , Neoplasias Experimentales , Securina/genética , Vía de Señalización WntRESUMEN
OBJECTIVE: Frequent loss of expression of platelet factor 4 (PF4) in multiple myeloma (MM) was revealed in several previous researches. The predictive analysis of serum PF4 level in newly diagnosed MM has not been well elucidated. This study is to assess if serum PF4 could be a prognostic factor in predicting treatment response and survival of MM treated with thalidomide and VAD regimens. METHODS: Sera of 122 MM were gained pre- and post-treatment of chemotherapy and oral thalidomide. Serological PF4 measurements were performed by ELISA. Kaplan-Meier method was employed for survival analysis. Log rank test was used significance analysis. Multivariate analysis of overall survival used Cox-regression. RESULTS: Our data showed that the median serum PF4 concentration was negatively associated with MM response and a significant correlation between serum PF4 level and unfavorable clinical features (ß2-microglobulin, ISS stage, del17p and creatinine). MM with lower serum PF4 concentration at diagnosis were prone to gain complete remission and very good partial remission after two courses of chemotherapy. Besides del17p, ß2-microglobulin, treatment response, the low serum PF4 concentration was an independent variable associated with a poor overall survival by univariate analysis and multivariate analysis. CONCLUSIONS: We speculate serum PF4 is a promising response and prognostic factor in newly diagnosed MM treated with thalidomide and VAD regimens.