CD133 as a regulator of cancer metastasis through the cancer stem cells

Liou, Geou-Yarh

doi:10.1016/j.biocel.2018.10.013

Cited by 97 publications

(78 citation statements)

References 89 publications

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“…Note that KMT2A here could represent expression from normal KMT2A, but in the case of MLLr leukemias will also include MLL-AF4 expression. Interestingly, the PROM1 gene (coding for CD133) is in cluster 2, which matches previous work identifying PROM1 as an overexpressed target of MLL-AF4 that is also more generally expressed in cancer stem cells (84)(85)(86).…”

Section: All and Aml Patient Sub-network Highlight Core Central Trasupporting

confidence: 87%

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

Harman

Thorne

Jamilly

et al. 2020

Preprint

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ABSTRACTRegulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than studying single TF binding events in isolation. Chromosomal translocations of the Mixed Lineage Leukemia gene (MLL) produce MLL fusion proteins such as MLL-AF4, causing poor prognosis acute lymphoblastic leukemias (ALLs). MLL-AF4 is thought to drive leukemogenesis by directly binding to genes and inducing aberrant overexpression of key gene targets, including anti-apoptotic factors such as BCL-2. However, this model minimizes the potential for circuit generated regulatory outputs, including gene repression. To better understand the MLL-AF4 driven regulatory landscape, we integrated ChIP-seq, patient RNA-seq and CRISPR essentiality screens to generate a model GRN. This GRN identified several key transcription factors, including RUNX1, that regulate target genes using feed-forward loop and cascade motifs. We used CRISPR screening in the presence of the BCL-2 inhibitor venetoclax to identify functional impacts on apoptosis. This identified an MLL-AF4:RUNX1 cascade that represses CASP9, perturbation of which disrupts venetoclax induced apoptosis. This illustrates how our GRN can be used to better understand potential mechanisms of drug resistance acquisition.Graphical abstract captionA network model of the MLL-AF4 regulatory landscape identifies feed-forward loop and cascade motifs. Functional screening using CRISPR and venetoclax identified an MLL-AF4:RUNX1:CASP9 repressive cascade that impairs drug-induced cell death.

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Section: All and Aml Patient Sub-network Highlight Core Central Trasupporting

confidence: 87%

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

Harman

Thorne

Jamilly

et al. 2020

Preprint

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“…CD133, encoded by the PROM1 gene, is a pentaspan transmembrane glycoprotein of great potential value as a pancancer target as it is commonly associated with cancer stem cells in multiple different tumor types, including leukemia These authors contributed equally: Laura Godfrey, Nicholas T. Crump [1,2]. Proof-of-principle studies have shown that targeting CD133 can be used to deliver nanoparticles to gastric stem cells [3], or for chimeric antigen receptor T cell therapy in acute lymphoblastic leukemias (ALL) caused by rearrangements of the Mixed Lineage Leukemia (MLL) gene [4].…”

Section: Introductionmentioning

confidence: 99%

H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

et al. 2020

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MLL gene rearrangements (MLLr) are a common cause of aggressive, incurable acute lymphoblastic leukemias (ALL) in infants and children, most of which originate in utero. The most common MLLr produces an MLL-AF4 fusion protein. MLL-AF4 promotes leukemogenesis by activating key target genes, mainly through recruitment of DOT1L and increased histone H3 lysine-79 methylation (H3K79me2/3). One key MLL-AF4 target gene is PROM1, which encodes CD133 (Prominin-1). CD133 is a pentaspan transmembrane glycoprotein that represents a potential pan-cancer target as it is found on multiple cancer stem cells. Here we demonstrate that aberrant PROM1/CD133 expression is essential for leukemic cell growth, mediated by direct binding of MLL-AF4. Activation is controlled by an intragenic H3K79me2/3 enhancer element (KEE) leading to increased enhancer-promoter interactions between PROM1 and the nearby gene TAPT1. This dual locus regulation is reflected in a strong correlation of expression in leukemia. We find that in PROM1/CD133 non-expressing cells, the PROM1 locus is repressed by polycomb repressive complex 2 (PRC2) binding, associated with reduced expression of TAPT1, partially due to loss of interactions with the PROM1 locus. Together, these results provide the first detailed analysis of PROM1/CD133 regulation that explains CD133 expression in MLLr ALL.

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“…It may be caused by the regulation of cell growth and proliferation, which causes serious disorder. At the same time, the abnormal expression of tumor related genes, abnormal activation of cell signal transduction, cell proliferation cycle, and cell proliferation cycle were also involved in many aspects [15][16][17]. Cell growth and proliferation in human body are affected and controlled by many factors [18,19].…”

Section: Discussionmentioning

confidence: 99%

Clinical significance of high expression of stanniocalcin-2 in hepatocellular carcinoma

Wang

et al. 2019

Bioscience Reports

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To investigate the significance of stanniocalcin-2 (STC2) expression in hepatocellular carcinoma (HCC) tissues and adjacent tissues. Levels of STC2 in HCC tissue were detected in 200 HCC patients tissues and adjacent tissues as controls by immunohistochemistry technique (IHC) and reverse transcriptase-PCR (RT-PCR). Single factor analysis was used to study the relationship between expression of STC2 mRNA and protein and clinicopathological features of HCC. Multifactor Cox survival analysis was used to relationship between the expression of STC2 and overall survival of postoperative patients with HCC. IHC staining showed that the expression of STC2 protein rate was 81.00% (163/200). And the positive rate of adjacent tissues was 29.00% (58/200). Western blot showed that the expression of STC2 protein in HCC was significantly higher than that in the adjacent tissues (P<0.05). RT-PCR showed that the positive rates of STC2 mRNA expression in HCC were 75.50% (151/200), which was significantly higher than that in adjacent tissues 14.50% (29/200) (P<0.05). Both STC2 mRNA and protein expression are related to tumor diameter, stage, tumor metastasis, carcinoma emboli in the portal vein and the degree of tumor differentiation in HCC. The HCC patients with higher expression of STC2 had shorter median survival time. STC2 expression, tumor diameter, carcinoma emboli in the portal vein, tumor differentiation degree, and tumor stage were independent factors affecting the overall survival of postoperative patients. The high expression of STC2 mRNA and protein expression in HCC may be associated with the occurrence, development, and prognosis of HCC. STC2 may also be possible to help developing new therapeutic strategies for HCC.

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CD133 as a regulator of cancer metastasis through the cancer stem cells

Cited by 97 publications

References 89 publications

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

Phenotypic analysis of an MLL-AF4 gene regulatory network reveals indirect CASP9 repression as a mode of inducing apoptosis resistance

H3K79me2/3 controls enhancer–promoter interactions and activation of the pan-cancer stem cell marker PROM1/CD133 in MLL-AF4 leukemia cells

Clinical significance of high expression of stanniocalcin-2 in hepatocellular carcinoma

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