Role of LRF/Pokemon in lineage fate decisions

Lunardi, Andrea; Guarnerio, Jlenia; Wang, Guocan; Maeda, Takahiro; Pandolfi, Pier Paolo

doi:10.1182/blood-2012-11-292037

Cited by 59 publications

(58 citation statements)

References 95 publications

(130 reference statements)

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“…Since undifferentiated sarcomas have been suggested to originate through the combined deregulation in adult MSCs of genes involved in cellular proliferation/apoptosis (such as p53), and genes implicated in the regulation of stem cell differentiation (29, 30), we decided to couple two known regulators of stem cells maintenance and differentiation with the loss of p53. The regulators enrolled in the platform were PML (31) and LRF/Pokemon [encoded by the gene ZBTB7A ( Zinc finger and BTB domain-containing protein 7A)] , which is emerging as one of the master regulators of differentiation for both hematopoietic and non-hematopoietic stem/progenitor cells, and has been attributed oncogenic or tumor suppressive functions depending on the specific cellular context (32). While Pml knockdown in p53-null MSCs did not trigger neoplastic transformation, adult p53-null MSCs knocked down for Lrf, showed features of neoplastic transformation in vitro (Fig.…”

Section: Resultsmentioning

confidence: 99%

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A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells

et al. 2015

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The regulatory factors governing adult mesenchymal stem cells (MSCs) physiology and their tumorigenic potential are still largely unknown, which substantially delays the identification of effective therapeutic approaches for the treatment of aggressive and lethal form of MSC-derived mesenchymal tumors, such as undifferentiated sarcomas. Here we have developed a novel platform to screen and quickly identify genes and pathways responsible for adult MSCs transformation, modeled undifferentiated sarcoma in vivo, and, ultimately, tested the efficacy of targeting the identified oncopathways. Importantly, by taking advantage of this new platform, we demonstrate the key role of an aberrant LRF-DLK1-SOX9 pathway in the pathogenesis of undifferentiated sarcoma with important therapeutic implications.

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Section: Resultsmentioning

confidence: 99%

“…LRF/Pokemon has been described in the stemness maintenance/differentiation in different cell lineages (32), however, nothing is known about its role in adult MSCs. For this reason, we first investigated the possibility that Lrf could trigger sarcomagenesis by blocking the differentiation capacity of MSCs.…”

Section: Resultsmentioning

confidence: 99%

A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells

et al. 2015

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“…ZBTB7A expression was increased in miR-150 CRISPR cells but not in control nontargeting CRISPR cells expressing KLF4. ZBTB7A is a putative miR-150 target as predicted by Targetscan (69), with documented roles in hematopoietic development (70). The role of miR-150 in controlling these genes should be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Morris

Cummings

Korb

et al. 2016

Molecular and Cellular Biology

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bAcute myeloid leukemia (AML) is characterized by increased proliferation and blocked differentiation of hematopoietic progenitors mediated, in part, by altered myeloid transcription factor expression. Decreased Krüppel-like factor 4 (KLF4) expression has been observed in AML, but how decreased KLF4 contributes to AML pathogenesis is largely unknown. We demonstrate decreased KLF4 expression in AML patient samples with various cytogenetic aberrations, confirm that KLF4 overexpression promotes myeloid differentiation and inhibits cell proliferation in AML cell lines, and identify new targets of KLF4. We have demonstrated that microRNA 150 (miR-150) expression is decreased in AML and that reintroducing miR-150 expression induces myeloid differentiation and inhibits proliferation of AML cells. We show that KLF family DNA binding sites are necessary for miR-150 promoter activity and that KLF2 or KLF4 overexpression induces miR-150 expression. miR-150 silencing, alone or in combination with silencing of CDKN1A, a well-described KLF4 target, did not fully reverse KLF4-mediated effects. Gene expression profiling and validation identified putative KLF4-regulated genes, including decreased MYC and downstream MYC-regulated gene expression in KLF4-overexpressing cells. Our findings indicate that decreased KLF4 expression mediates antileukemic effects through regulation of gene and microRNA networks, containing miR-150, CDKN1A, and MYC, and provide mechanistic support for therapeutic strategies increasing KLF4 expression.A cute myeloid leukemia (AML) is characterized by increased self-renewal of leukemia stem or progenitor cells and a failure of differentiation to mature myeloid cells. Normal hematopoietic cell differentiation and proliferation are regulated by the expression and interaction of specific transcription factors (1, 2), which are altered in AML (3-5). Elucidation of the genomic landscape of AML has further highlighted that alterations in myeloid transcription factors play a significant role in leukemogenesis (4). Recent attention has focused on the role of aberrant expression of the Krüppel-like factor (KLF) family of transcription factors in cancer (5). This family includes 17 different isoforms that bind to GCrich regions of DNA via three zinc finger domains and regulate the transcriptional activity of target genes by using two glutaminerich transactivation domains (5). KLF4 regulates differentiation of epidermal and vascular smooth muscle cells (6, 7), as well as cellular reprogramming to induce pluripotent stem cells (8). In normal hematopoiesis, KLF2 and KLF4 regulate myeloid differentiation and KLF4 expression induces CDKN1A (p21), which contributes to cell cycle arrest (9-13). In T-cell acute lymphoblastic leukemia (T-ALL) (14) and B-cell lymphomas, KLF4 has been described as a tumor suppressor regulating proliferation, apoptosis, and differentiation (15). A recent study showed that the homeobox transcription factor CDX2 represses KLF4 in myeloid leukemia cells (16). The investigators also observed that C...

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“…31 In Table 2 The top 15 GO functional enrichment of 370 collaboratively regulated genes in cluster 6 at five time points of SCI in rats addition, a former study has demonstrated that LRF is expressed in the developing CNS and has a critical role of oligodendrocyte differentiation during the development of myelination in the CNS. 32 As we all know, regulated by neuro-inflammation, oligoden-drocytes could deteriorate the development of SCI by causing axonal conduction abnormal. 33 The ability of neurons to regenerate their axons after nerve injury requires extensive alterations in gene transcription.…”

Section: Construction Of Transcriptional Regulatory Networkmentioning

confidence: 99%

Comparative analysis of molecular mechanism of spinal cord injury with time based on bioinformatics data

et al. 2015

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Objectives: This study was designed to explore the molecular mechanisms of spinal cord injury (SCI) with time. Methods: The gene expression profile (GSE45006) including four non-injured spinal cord samples as sham-control group and 20 thoracic transected spinal cords samples as experimental group at different times was downloaded from Gene Expression Omnibus database. The time-course changes of the SCI-related differentially expressed genes (DEGs) were identified. In addition, time-series expression profile clusters of DEGs were obtained, followed by gene ontology (GO) and pathway enrichment analysis of the DEGs. Moreover, the transcriptional regulatory network was constructed. Results: There were 1420, 492, 743, 568 and 533 DEGs respectively at d1, d3, w1, w2 and w8 compared with that of sham group. Importantly, 101 overlapped regulated DEGs were identified at five time points and 370 collaboratively regulated genes were identified in cluster 6. Significant functions of overlapped regulated DEGs were obtained including response to wounding and developmental process. In addition, the DEGs, such as CD14 molecule (CD14) and chemokine (C-C motif) ligand 2 (CCL2), were enriched mostly in the pathways related to tuberculosis, phagosome and NF-kappa B signaling pathway. From the transcriptional regulatory network, we identified some transription factors (TFs), including member of E26 transformation-specific (ETS) oncogene family (ELK1) and zinc finger and BTB domain containing 7A (Zbtb7a). Conclusion: The DEGs related to immune response during SCI may provide underlying targets for treatment of SCI. Moreover, the TFs ZBTB7A and ELK1 and their target gene (dual specificity phosphatase 18 (DUSP18)) might be therapeutic targets for the treatment of SCI.

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Role of LRF/Pokemon in lineage fate decisions

Cited by 59 publications

References 95 publications

A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells

A Genetic Platform to Model Sarcomagenesis from Primary Adult Mesenchymal Stem Cells

Deregulated KLF4 Expression in Myeloid Leukemias Alters Cell Proliferation and Differentiation through MicroRNA and Gene Targets

Comparative analysis of molecular mechanism of spinal cord injury with time based on bioinformatics data

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