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Genome-wide identification of beta-catenin related genes in CD34 + Hematopoietic Stem and Progenitor Cells of patients with Acute Myeloid Leukemia

ABSTRACT: Background: Acute myeloid leukaemia is a disease characterised by the accumulation of large number of aberrant, immature myeloid cells in the bone marrow and peripheral blood as a result of a variety of genetic alterations in early haematopoietic stem cells. Normal stem cells, which have the ability to renew themselves, can undergo neoplastic transformation as a result of mutations in signalling pathway genes, changes in epigenetics or gene expression levels. The gene expression levels of beta-catenin, a key element of the Wnt signalling pathway, which is particularly active during embryogenesis and in various cancers, have been widely studied in the literature. In these studies, which were consistent with each other, serious differences in beta-catenin gene expression levels were found in AML patients. On this basis, our aim of this study was to determine beta-catenin gene expression levels in AML patients. In the next part of the study, it is planned to compare the genes between AML patient samples grouped according to beta-catenin gene expression levels by DNA microarray analysis. When the gene group identified in this way is combined with the genes in the healthy control group, the aim is to determine the genes and pathways that are associated with beta-catenin in AML patients. Material and Method: In this study, beta-catenin gene expression levels were determined in bone marrow/blood CD34+ cells of 19 AML patients and 3 healthy controls by qRT-PCR. Transcriptome analysis was performed on AML patient samples grouped according to beta-catenin expression levels. After transcriptome analysis, differentially expressed genes (DEGs) were identified using a 1.5-fold change threshold. DEGs were further investigated using the online analysis tools DAVID, GO, KEGG and STRING. Results: In this study, the mRNA analysis showed that beta-catenin levels varied between AML samples. Based on these results, the AML samples were divided into 2 groups: high and low beta catenin. The transcriptome profiles of the AML samples showed different molecular signature profiles according on their beta-catenin levels (high-low) when compared to the healthy control group. In our study, it was found that hub genes related to cell cycle, ribosome biogenesis and transcription factor pathways were beta-catenin-related genes and were prominent in the group of AML patients with high beta-catenin levels. Conclusion: It is suggested that the identification of beta-catenin-related gene profiles in AML may help to select new molecular therapeutic targets for the treatment of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245305 | GEO | 2024/07/17

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia (AML) propagates as a cellular hierarchy which is maintained by a rare subpopulation of self-renewing leukemia-initiating cells (LICs). These LICs phenotypically resemble HSCs and early myeloid progenitors, and they are functionally defined by their ability to reconstitute AML in xenografted mice. Common transcriptional regulators are believed to drive self-renewal of LICs and normal stem cells. Examples include the histone methyltransferase, MLL and its main targets, the transcription factors HOXA9 and MEIS1; the polycomb group protein, BMI-1; and the Wnt/β-catenin signaling pathway4-9. In AML patients, LICs have been shown to share broad gene expression signatures with hematopoietic stem cells (HSCs) and, in some cases, with embryonic stem cells (ESCs). Moreover, increased expression of these stem cell signatures has been linked to tumor aggressiveness. Elucidating the molecular determinants of stem cell properties in LICs has the potential to improve AML therapy and clarify the relationship between cancer and stem cell biology in general. Here we show that the propagation of LICs in AML depends on Zfx, a transcription factor required for the self-renewal of ESCs and HSCs. Using mouse models, we found that Zfx is required for AML propagation and LIC maintenance. We defined a Zfx-driven gene expression program in murine LICs that correlates with existing stem cell-related gene expression signatures in AML patients. Using a novel, stroma-based RNAi screening strategy, we identified functionally important Zfx target genes. Two of these genes – FAM92A1 and DOCK7 - are required for human AML cell propagation; moreover, their expression levels strongly correlate with AML patient survival across the full spectrum of AML subtypes. Together, our results characterize a novel gene expression program that orchestrates critical stem cell properties of LICs, and drives aggressiveness of AML. Independent primary MLL-AF9 AML cell lines were created carrying the tamoxifen inducible Cre-ER transgene and either the Zfx wild-type (wt/y) (lines 10977, 10980) or the Zfx conditional (Zfx fl/y) allele (lines 10949, 10950, 10986). AML cells generated from each line were isolated from moribund mice and cultured with or without 4-hydroxytamoxifen for 72 hours to induce Cre. After Cre induction, c-Kit + cells were purified by FACS and processed for microarray studies.

Project description:For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively). For developing a accurate prognostic signature for “pan-driver-gene-negative” LUAD, we employed whole genome microarray expression profiling as a discovery platform to identify candidate genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “pan-driver-gene-negative” LUAD. Furthermore, the Wnt/β-catenin-pathway-based gene expression profiles revealed 39 transcripts differentially expressed by diagnostic status, with 30 genes being upregulated and 9 downregulated. Finally, a Wnt/β-catenin-pathway-based signature (CSDW) comprising 4 genes (β-catenin, Wnt2b, DVL3 and SOX9) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival (hazard ratio [HR] 10·42, 6·46–16·79; p<0·001) than patients with low-risk scores. The CSDW performance was further validated in an internal cohort and two external cohorts. The protein expression levels of several hub genes, including β-catenin, SOX9, DVL3 and Wnt2b, were strongly correlated with lymphatic metastasis and distant organ metastasis. Furthermore, a nomogram comprising CSDW and other variables was generated to predict progression-free survival and overall survival in the training cohort and performed well in the three independent validation cohorts (C-index: 0·725, 0·697 and 0·693, respectively).

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Genome-wide identification of beta-catenin related genes in CD34 + Hematopoietic Stem and Progenitor Cells of patients with Acute Myeloid Leukemia

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