Identification of a subset of patients with acute myeloid leukemia characterized by long-term<i>in vitro</i>proliferation and altered cell cycle regulation of the leukemic cells

Hatfield, Kimberley Joanne; Reikvam, Håkon; Bruserud, Øystein

doi:10.1517/14728222.2014.957671

Cited by 25 publications

(23 citation statements)

References 72 publications

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“…In agreement with previous results [13], the capacity of long-term AML cell proliferation in the absence of supportive cells was not associated with the differentiation status of the primary AML cells at the time of diagnosis, i.e., cultures with and without this capacity did not differ with regard to morphological signs of differentiation (FAB classification) or expression of the CD34 stem cell marker. Furthermore, apart from cell number colony formation after long-term culture appeared to be independent of common prognostic factors such as patient age, hemoglobin levels, peripheral blood blast count, cytogenetics, NPM1 mutations, and secondary or relapsed versus de novo AML (an overview of patient details is provided in Supplementary Table S1).…”

Section: Resultssupporting

confidence: 92%

The Capacity of Long-Term In Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome

Brenner

Aasebø

Hernandez-Valladares

et al. 2019

Cancers

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Acute myeloid leukemia (AML) is an aggressive malignancy, which is highly heterogeneous with regard to chemosensitivity and biological features. The AML cell population is organized in a hierarchy that is reflected in the in vitro growth characteristics, with only a minority of cells being able to proliferate for more than two weeks. In this study, we investigated the ability of AML stem cells to survive and proliferate in suspension cultures in the presence of exogenous mediators but without supporting non-leukemic cells. We saw that a high number of maintained stem cells (i.e., a large number of clonogenic cells after five weeks of culture) was associated with decreased overall survival for patients receiving intensive chemotherapy; this prognostic impact was also detected in the multivariate/adjusted analysis. Furthermore, the patients with many clonogenic cells presented more frequently with mutations in transcription-related genes, and also showed a higher abundance of proteins involved in transcription at the time of diagnosis. In conclusion, the growth characteristics of the long-term proliferating leukemic stem cells seem to have an independent prognostic impact in human AML, and these characteristics appear to be reflected by the mutational landscape and the proteome of the patients at the time of diagnosis.

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Section: Resultssupporting

confidence: 92%

The Capacity of Long-Term In Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome

Brenner

Aasebø

Hernandez-Valladares

et al. 2019

Cancers

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“…In cytological experiments, the knockdown of DLGAP5 caused inhibition of proliferation, migration and invasion of NSCLC cells (10). Previous studies have also shown that the expression levels of DLGAP5 are upregulated in bladder (11), prostate (12) and liver cancer (13), as well as leukemia (14) were associated with poor prognosis. In the present study, DLGAP5 was identified to be a hub gene in GEO and Gene Expression-Based Outcome for BC Online (GOBO) databases.…”

Section: Introductionmentioning

confidence: 91%

Elevated mRNA expression levels of DLGAP5 are associated with poor prognosis in breast cancer

Dong

Zhang

et al. 2020

Oncol Lett

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Breast cancer is the most commonly diagnosed type of cancer and one of the leading causes of cancer-associated mortality in women. In addition, the underlying molecular mechanisms of the occurrence and development of breast cancer requires further investigation. In the present study, bioinformatics analysis was performed to identify differentially expressed genes (DEGs) between breast cancer and normal breast tissues to investigate the underlying molecular mechanisms. In addition, reverse transcription-quantitative PCR and immunohistochemistry (IHC) were performed to investigate the protein and mRNA expression levels of a specific DEG, discs large-associated protein 5 (DLGAP5). A Cell Counting Kit-8 assay and flow cytometry analysis were used to assess the effects of DLGAP5 on cell proliferation. In total, 85 DEGs were identified in the three Gene Expression Omnibus datasets, including 40 upregulated and 45 downregulated genes. In addition, 30 hub genes were identified following the construction of a protein-protein interaction network, and 28 of the 30 hub genes were established to be indicators of breast cancer prognosis. DLGAP5 was highly expressed in breast cancer specimens, and its expression levels were correlated with clinical stage and lymph node status. In addition, downregulation of DLGAP5 repressed the proliferation of breast cancer MDA-MB-231 cells and induced cell cycle arrest. Additionally, DLGAP5 was identified to be localized in the mitochondria, and the presence of a conserved microtubule-associated proteins 1A/1B light chain 3B-interacting region motif suggested that DLGAP5 may serve a role in mitophagy. The present results demonstrated an association between DLGAP5 expression levels and the clinicopathological characteristics of patients with breast cancer using IHC. In conclusion, DLGAP5 may be a promising target in the diagnosis and treatment of breast cancer.

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“…The downregulation of CCNF was also established in B-cell ALL (42). NUSAP1 and CCNF were associated with altered cell cycle in acute myeloid leukemia (43), therefore providing further evidence of the role of the two genes in cell cycle modulation. These results collectively suggest that the 3 genes ( MKI67 , NUSAP1 and CCNF ) mediate cell cycle processes and may have regulatory roles in the B-cell ALL progression.…”

Section: Discussionmentioning

confidence: 91%

Potential therapeutic targets and small molecular drugs for pediatric B-precursor acute lymphoblastic leukemia treatment based on microarray data

Kong

Zhang

et al. 2017

Oncology Letters

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The current study investigated the molecular mechanisms underlying pediatric acute lymphoblastic leukemia (ALL) and screened for small molecular drugs as supplementary drugs to aid current therapy. Gene expression data of Gene Expression Omnibus (GEO) DataSet GSE42221, which consists of 7 primary human B-precursor samples and 4 control B-cell progenitor lymphoblast samples from patients with pediatric ALL, were downloaded from the public GEO database. Linear Models for Microarray Analysis package for R statistical software was used to identify differentially expressed genes (DEGs). Subsequently, biclustering analysis of DEGs was performed using pheatmap package for R. Functional enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization and Integrated Discovery tool. Additionally, Search Tool for the Retrieval of Interacting Genes software was used to screen protein-protein interactions (PPIs) of the DEGs, and Connectivity Map database was employed to obtain small-molecule drugs that were significantly associated with DEGs. In total, 116 genes were identified as DEGs in pediatric ALL, including 56 downregulated and 60 upregulated genes. Functional enrichment analysis identified that upregulated DEGs, including marker of proliferation Ki-67, cyclin F and nucleolar and spindle associated protein 1, were significantly enriched in mesenchymal cell differentiation and development processes, whilst downregulated DEGs, including bone marrow morphogenetic protein 2, semaphoring 3F and ephrin B1 were enriched in cell cycle process. Amongst the DEGs, 169 PPIs were identified. Notably, carbimazole and quinostatin were associated with DEGs. Additionally, a number of DEGs were targeted by the two drugs, including signal transducer and activator of transcription 3, nucleolar and spindle associated protein 1 and cell division cycle 20. Mesenchymal cell differentiation and development as well as cell cycle processes may be important for pediatric ALL. Quinostatin may be used as a potent supplementary drug for treating pediatric ALL.

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Identification of a subset of patients with acute myeloid leukemia characterized by long-termin vitroproliferation and altered cell cycle regulation of the leukemic cells

Abstract: We identified a subset of AML patients characterized by long-term in vitro cell proliferation and altered expression of cell cycle regulators that may be potential candidates for treatment of AML.

Cited by 25 publications

References 72 publications

The Capacity of Long-Term In Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome

The Capacity of Long-Term In Vitro Proliferation of Acute Myeloid Leukemia Cells Supported Only by Exogenous Cytokines Is Associated with a Patient Subset with Adverse Outcome

Elevated mRNA expression levels of DLGAP5 are associated with poor prognosis in breast cancer

Potential therapeutic targets and small molecular drugs for pediatric B-precursor acute lymphoblastic leukemia treatment based on microarray data

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