High expression of HMGA2 independently predicts poor clinical outcomes in acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Marquis M
PROVIDER: S-EPMC6066481 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
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Project description:Heparan sulfate proteoglycan 2 (HSPG2), also known as perlecan, is a large multi-domain extracellular matrix proteoglycan, which contributes to the invasion, metastasis and angiogenesis of solid tumor. However, very little is known about the effect of HSPG2 on acute myeloid leukemia (AML). This study aims to investigate the prognostic value of the HSPG2 gene in terms of overall survival and leukemia-free survival in patients with AML. Bone marrow mononuclear cells (BMMCs) from 4 AML patients and 3 healthy controls were processed for RNA-Sequencing (RNA-seq). The mRNA expression level of HSPG2 in BMMCs and CD34+ hematopoietic stem/progenitor cells (HSPC) obtained from enrolled participants and human leukemic cell lines was detected by RT-qPCR. Then the correlations between the expression of HSPG2 and a variety of important clinical parameters, such as median white blood cell (WBC) count and bone marrow (BM) blasts, were further analyzed. The expression level of HSPG2 was significantly upregulated in AML patients at the time of diagnosis, downregulated after complete remission and then elevated again at relapse. Moreover, HSPG2 expression was associated with median WBC count (P < 0.001), median hemoglobin (P = 0.02), median platelet count (P = 0.001), and BM blasts (P < 0.001) in AML patients. Patients with high HSPG2 expression had both worse overall survival (OS) (P = 0.001) and poorer leukemia-free survival (LFS) (P = 0.047). In the multivariate analysis model, HSPG2 was identified as an independent prognostic biomarker of AML. Taken together, these results indicate that HSPG2 overexpression was associated with poor prognosis in AML patients, and may be a prognostic biomarker and therapeutic target of AML.
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Project description:BackgroundAcute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined.MethodsIn this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML.ResultsHSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA).ConclusionsOur research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.
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Project description:BACKGROUND:Acute myeloid leukemia (AML) is a heterogeneous disease in terms of genetic basis, clinical, biological and prognostic, and is a malignant clonal disease of leukemia stem cells (LSCs). Nearly half of adult AML patients exhibit a cytogenetic normal acute myeloid leukemia (CN-AML). The expression level of NCALD gene was associated with the prognosis of ovarian cancer and non-small cell lung cancer (NSCLC). The expression level of NCALD gene is still unclear in the prognosis of patients with AML. METHOD:We integrated 5 independent datasets totally 665 AML patients (497 CN-AML patients) to analyzed relation between NCALD gene expression and the clinical FAB classification, gene mutation, therapy, prognosis of CN-AML. We analyzed the NCALD gene expression with the prognosis and LSC of 165 AML patients from The Cancer Genome Atlas (TCGA) dataset and 78 AML patients from GEO dataset. RESULTS:High NCALD-expressing CN-AML patients were associated with poor event-free survival (EFS) and overall survival (OS) compared to low NCALD expression (EFS, P?<?0.0001, OS, P?<?0.0001). In AML patients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), high NCALD expression was associated with poor survival prognosis in EFS and OS (EFS, P?<?0.0051, OS, P?=?0.028). Post-chemotherapy in AML patients, high NCALD expression led a worse prognosis in EFS and OS (EFS, P?=?0.011; OS, P?=?0.0056). In multivariate analysis, high NCALD expression was an independent prognostic factor that predicts shorter EFS and OS (EFS, P?=?3.84E-05, OS, P?=?8.53E-05) of CN-AML. CONCLUSION:Our results indicate that high expression of NCALD gene is a poor prognostic factor for CN-AML. NCALD can be considered as independent predictors of CN-AML patients and can be used as a biomarker for the prognosis of CN-AML.
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Project description:Objectives: VAV family genes (VAV1, VAV2, and VAV3) are associated with prognosis in various cancers; however, they have not been evaluated in acute myeloid leukemia (AML). In this study, the prognostic value of VAV expression in AML was evaluated by a single-center study in combination with bioinformatics analyses. Methods: The expression and prognostic value of VAVs in patients with AML were investigated using various databases, including GEPIA, CCLE, EMBL-EBI, UALCAN, cBioPortal, STRING, and DAVID. Blood samples from 35 patients with AML (non-M3 subtype) and 13 benigh individuals were collected at our center. VAV expression levels were detected by real-time quantitative PCR (RT-qPCR) and western blotting. Clinical data were derived from medical records. Results: Based on data from multiple databases, the expression levels of VAV1, VAV2, and VAV3 were significantly higher in AML than in control tissues (P < 0.05). RT-qPCR and western blotting results showed that VAV expression in mRNA and protein levels were higher in patients with AML that in the control group (P < 0.05). Complete remission rates were lower and risks were higher in patients with AML with high VAV1 expression than with low VAV1 expression (P < 0.05). High levels of VAV2, VAV3, and VAV1 were related to a poor overall survival, and this relationship was significant for VAV1 (P < 0.05). High expression levels of genes correlated with VAV1, such as SIPA1, SH2D3C, and HMHA1 were also related to a poor prognosis in AML. Functional and pathways enrichment analyses indicated that the contribution of the VAV family to AML may be mediated by the NF-κB, cAMP, and other pathways. Conclusion: VAVs were highly expressed in AML. In particular, VAV1 has prognostic value and is a promising therapeutic target for AML.
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Project description:AimsThis study aimed to assess the associations between clinical parameters, long-term outcomes, and expression of chemokine receptor CXCR2 in patients with acute myeloid leukemia (AML).MethodsFrom May 2013 to May 2017, 83 adult patients newly diagnosed with AML in the Affiliated Hospital of BeiHua University and Jilin Chemical Hospital, were enrolled in this study. The expression of CXCR2 in bone marrow mononuclear cells was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Clinical information and RNA-sequencing datasets of The Cancer Genome Atlas (TCGA) (n = 136) were obtained. The associations between clinical parameters, prognosis, and CXCR2 expression were analyzed.ResultsFrom both cohorts, patients with AML with M4 and M5 subtypes showed higher CXCR2 expression levels than those with other French-American-British (FAB) subtypes. Patients with extramedullary leukemia infiltration had higher CXCR2 levels than those without. In our cohort, patients with high CXCR2 levels (⩾2.099) had lower relapse-free survival (RFS) (p < 0.000001) and overall survival (OS) (p = 0.000107) than those with low levels (<2.099). High CXCR2 levels (⩾2.082) also indicated a poor OS in the TCGA cohort but only in patients younger than 65 years (5-year OS: 7.7% versus 29.9% in those with CXCR2 levels < 2.082). High CXCR2 levels independently predicted poor prognosis in AML patients, as determined by Cox proportional hazards models.ConclusionOur results suggest that high CXCR2 expression associates with the monocytic lineage of AML and is an independent risk factor for poor patient prognosis.
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