ABSTRACT
BACKGROUND: High expression of amyloid-ß (Aß) in periodontal tissue could contribute to exacerbating the development of both periodontitis and Alzheimer's disease (AD). Porphyromonas gingivalis (P. gingivalis) as a periodontal pathogen expresses msRNAs, which can regulate gene transcription in host cells. OBJECTIVE: The aim of this study is to reveal the mechanism of msRNA P.G_45033, a high copy msRNA in P. gingivalis, inducing Aß expression in macrophages, and provide a new insight to explain the development of periodontitis, and also to explain the role of periodontal infection on AD. METHODS: The levels of glucose consumption, pyruvate and lactate productions in macrophages after transfection with msRNA P.G_45033 were detected. Miranda, TargetScan, and RNAhybrid databases were used to predict the target gene of msRNA P.G_45033, and GO analysis was conducted to describe the functions of the overlapping ones. RT2 glucose-metabolism PCR Array was used to verify the relationship between msRNA P.G_45033 and the expression of genes related to glucose metabolism. The levels of histone Kla were detected using western blotting. The levels of Aß in the macrophages and the culture medium were detected by immunofluorescence and ELISA, respectively. RESULTS: The levels of glucose consumption, pyruvate and lactate productions were increased after transfection of msRNA P.G_45033 in macrophages. GO analysis revealed that target genes were enriched in the metabolic process. RT2 glucose-metabolism PCR Array showed the expression of genes associated with glycolysis. The results of western blotting showed that the level of histone Kla was increased in macrophages. The results of immunofluorescence and ELISA showed that Aß levels in macrophages and culture medium were increased after transfection. CONCLUSION: The present study revealed that msRNA P.G_45033 can induce Aß production by enhancing glycolysis and histone Kla in macrophages.
Subject(s)
Alzheimer Disease , Periodontitis , Humans , Histones/metabolism , Porphyromonas gingivalis , Macrophages/metabolism , Amyloid beta-Peptides/metabolism , Periodontitis/metabolism , Alzheimer Disease/metabolism , Glycolysis , Lactates , Pyruvates , Glucose/metabolismABSTRACT
BACKGROUND: Transcription factor SOX6 belongs to Sry-related high-mobility-group box (SOX) family, has been reported to be downregulated and acts as a tumor-suppressor gene in various solid tumors, but in acute myeloid leukemia (AML) is incompletely understood. METHODS: The SOX6 expression was analyzed between AML patients and normal controls from public data and our research cohort. Correlations between SOX6 expression and clinical, genetic features together with survival were further analyzed. RESULTS: In both public and our present datasets, we demonstrated that SOX6 expression is notably downregulated in AML patients compared with normal controls. Moreover, the expression level of SOX6 was dynamic, along with the disease status. SOX6 was significantly decreased in relapsed/refractory AML compared with complete remission AML. Clinically, SOX6 underexpression was significantly correlated with bone marrow blasts, and WBC counts. Furthermore, decreased expression of SOX6 was more common in core binding factor AML (CBF-AML), rarely found in complex karyotype AML (CK-AML), and correlated with FLT3 mutations. By survival analyses, low-expression of SOX6 was associated with shorter overall survival (OS) and event-free survival (EFS) among cytogenetic normal AML (CN-AML) patients. Moreover, both univariate and multivariate analyses showed that low SOX6 expression was an independent unfavorable prognostic biomarker for CN-AML. CONCLUSIONS: Our findings indicated that SOX6 underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. SOX6 might be a valuable biomarker for risk stratification, predicting prognosis and relapse of AML.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Leukemia, Myeloid, Acute/pathology , Bone Marrow/metabolism , Survival Analysis , Prognosis , Leukocyte Count , Mutation , SOXD Transcription Factors/geneticsABSTRACT
BACKGROUND: Prickle planar cell polarity protein 1 (PRICKLE1), a core component of the non-canonical Wnt/planar cell polarity (PCP) pathway, was recently reported to be upregulated and correlated with poor prognosis in solid cancers. However, the effect of PRICKLE1 on acute myeloid leukemia (AML) remains unknown. This study aims to characterize the prognostic significance of PRICKLE1 expression in patients with AML. METHODS: RNA-seq was performed to compare mRNA expression profiles of AML patients and healthy controls. qRT-PCR and western blotting were used to analyze the expression of PRICKLE1 in AML patients and cell lines, and two independent datasets (TCGA-LAML and TARGET-AML) online were used to validate the expression results. The correlations between the expression of PRICKLE1 and clinical features were further analyzed. RESULTS: Our data showed that PRICKLE1 expression levels were markedly high in AML patients at the time of diagnosis, decreased after complete remission and increased again at relapse. Of note, PRICKLE1 was highly expressed in drug resistant AML cells and monocytic-AML patients. High PRICKLE1 expression was found in FLT3/DNMT3A/IDH1/IDH2-mutant AML and associated with poor prognosis. Furthermore, high expression of PRICKLE1 may be correlated with migration and invasion components upregulation in AML patients. CONCLUSIONS: These results indicated that high PRICKLE1 expression may be a poor prognostic biomarker and therapeutic target of AML.
Subject(s)
Gene Expression Regulation, Leukemic , Leukemia, Myeloid, Acute , Humans , LIM Domain Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Mutation , Prognosis , Remission Induction , Tumor Suppressor Proteins , Wnt Signaling PathwayABSTRACT
The glutamine amino acid transporter solute carrier family 38 member 1 (SLC38A1) is associated with the occurrence and progression of solid tumors. However, it has not yet been assessed in patients with hematologic malignancy. Herein, we investigated SLC38A1 expression and explored its clinical implications in acute myeloid leukemia (AML). The results showed that patients with high SLC38A1 expression had a lower mutation rate of NPM1 gene and higher incidence of adverse-risk karyotype (p = 0.0010 and 0.0051, respectively). Patients with a high level of SLC38A1 expression presented significantly shorter overall survival in whole-cohort, chemotherapy-only, and non-inv(16) AML (p = 0.0049, 0.0247, and 0.0005 respectively). Moreover, both univariate and multivariate analyses showed that high SLC38A1 expression was an independent unfavorable prognostic biomarker for AML (p = 0.0057 and 0.0483, respectively). In summary, our study revealed SLC38A1 as a valuable prognostic and predictive marker for AML. Further, glutamine transporter SLC38A1 might serve as a potential target for the development of novel therapeutic drugs in the treatment of AML.
Subject(s)
Amino Acid Transport System A/genetics , Gene Expression Regulation, Leukemic/genetics , Leukemia, Myeloid, Acute/genetics , Mutation/genetics , Adolescent , Adult , Aged , Biomarkers, Tumor/genetics , Child , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Nuclear Proteins/genetics , Nucleophosmin , Prognosis , Remission Induction , Young AdultABSTRACT
OBJECTIVE: To explore the clinical and laboratory characteristics of 5 patients with myeloid leukemia and t(12;22)(p13;q12). METHODS: Bone marrow cells were cultured for 24 h and analyzed by standard R-banding. Rearrangement of the MN1 gene was detected by fluorescence in situ hybridization (FISH) using dual color break-apart MN1 probes. MN1-ETV6 and ETV6-MN1 fusion genes were detected by reverse transcription polymerase chain reaction (RT-PCR). And the products were subjected to direct sequencing. RESULTS: Among the 5 patients, 2 had AML-M0, 2 had AML-M4, and 1 had CMM0L at the initial diagnosis. t(12;22)(p13;q12) was the primary abnormality among all patients. Rearrangements of MN1 gene were detected by FISH in all patients. MN1-ETV6 and ETV6-MN1 fusion genes were detected respectively in 4 and 3 patients. CONCLUSION: t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality in myeloid leukemia, and is related to poor prognosis. allo-SCT is valuable for patients with t(12;22)(p13;q12).
Subject(s)
Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 22 , Leukemia, Myeloid , Translocation, Genetic , Chromosome Banding , Cytogenetics , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myeloid/genetics , Oncogene Proteins, FusionSubject(s)
Chromosomes, Human/genetics , Fusion Proteins, bcr-abl/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Nuclear Proteins/genetics , Retinoic Acid Receptor alpha/genetics , Translocation, Genetic , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/diagnosis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , NucleophosminABSTRACT
Chronic myeloid leukemia (CML) is rare among children and adolescents. The early molecular response (EMR) is an important prognostic significance for adult CML patients. This study explored the impact of EMR on the prognosis in 40 children and adolescents with CML-CP treated with imatinib (IM). Our results showed that a high proportion of patients failed to achieve the BCR-ABL1/ABL1 International Scale (IS) ≤ 10% at 3 months. Children with a BCR-ABL1/ABL1 ≤ 10% at 3 months and <1% at 6 months increased the rate of achieving complete cytogenetic response (CCyR) and/or major molecular response (MMR) at 12 months compared to those with BCR-ABL1/ABL1 > 10%. With a median follow-up of 42 months, patients with BCR-ABL1/ABL1 ≤ 10% showed a better 4-year event-free survival (EFS). In summary, achieving BCR-ABL1/ABL1 IS ≤10% at 3 months and <1% at 6 months would increase the possibility of achieving MMR, CCyR at 12 months and had a better 4-year EFS. EMR is a reliable prognosticator for young CML patients treated with IM.
Subject(s)
Fusion Proteins, bcr-abl/genetics , Gene Expression Regulation, Leukemic/drug effects , Imatinib Mesylate/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Adolescent , Antineoplastic Agents/therapeutic use , Child , Female , Humans , Kaplan-Meier Estimate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Prognosis , Retrospective Studies , Time FactorsABSTRACT
t(12;22)(p13;q12) is a rare but recurrent chromosomal abnormality involving the ETS transcription factor ETV6 and meningioma 1 (MN1) genes. In this study, we analyzed the clinical, cytogenetic, and molecular features of five new patients with the t(12;22)/MN1-EVT6 who presented with acute myeloid leukemia or chronic myelomonocytic leukemia. We subsequently reviewed the literature and identified seven additional cases reported with t(12;22)/MN1-EVT6. Our data suggest that neoplasms carrying the t(12;22)/MN1-ETV6, although rare, can commonly present as myeloid neoplasms at the initial diagnosis, including acute myeloid leukemia (n = 8), myelodysplastic syndrome (n = 2), and myelodysplastic/myeloproliferative neoplasms (n = 2). There were five men and seven women with a median age of 43 years (range, 15-63 years) at initial diagnosis. Cytogenetics revealed t(12;22) as the sole abnormality in five patients, with the remaining seven patients harboring additional chromosomal aberrations. Of the five patients who received known therapy regimens, all of them had poor response to the idarubicin/mitoxantrone + cytarabine regimen. Of the seven patients with follow-up information, six patients died with a median overall survival time of only 5 months (range, 1-12 months) after the emergence of t(12;22). In summary, patients with t(12;22) are frequently associated with myeloid neoplasms, poor response to chemotherapy, and inferior outcome.
