Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma

Burkhart, Catherine; Cheng, Andy J.; Madafiglio, Janice; Kavallaris, Maria; Mili, Mario; Marshall, Glenn M.; Weiss, William A.; Khachigian, Levon M.; Norris, Murray D.; Haber, Michelle

doi:10.1093/jnci/djg045

Cited by 95 publications

(100 citation statements)

References 37 publications

(50 reference statements)

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“…Neuroblastoma tumourigenesis in these mice correlates with transgene dosage, and similarly to human neuroblastoma, we have also demonstrated amplification of the MYCN transgene. 6,16,17 The development and characterisation of unique isogenic cell lines from tumours arising in these transgenic mice further extends the utility of this model. Importantly, these cell lines displayed molecular and biological features characteristic of clinical neuroblastoma and in conjunction with the transgenic mice, the cell lines should prove valuable for basic and pre-clinical studies of neuroblastoma biology and treatment.…”

Section: Discussionmentioning

confidence: 97%

“…17 An identical immunostaining protocol was used to detect S100A6. The immunodetection of TH was modified by fixing the cytocentrifuged cells in 4% v/v paraformaldehyde/PBS for 10 min at room temperature.…”

Section: Fluorescent Immunocytochemistrymentioning

confidence: 99%

“…Human MYCN, murine odc and murine mrp1 gene expression was determined by real-time PCR analysis using the ΔΔC t method as previously described. 17 The primer and probe sequences for Human MYCN, murine odc, murine mrp1 and murine ACTB have been previously described. 17 Expression of the TH and S100A6 genes relative to the ACTB control was determined by 35 cycles of conventional RT-PCR with the following TH and S100A6 primer sequences: MTH43S 5′-GCTTCAGAAGAGCCGTCTCAGA-3′, MTH149A 5′-CTCCTTGCGGGCATCCT-3′; S100A6F 5′-TGGCTCCAAGCTGCAGG-3′, S100A6R 5′-CCCAGGAAGGCGACATACTC-3′.…”

Section: Rna Isolation and Gene Expression Analysismentioning

confidence: 99%

“…6,16,17 FISH analysis was performed to quantify MYCN transgene copy number in tissues and cell lines from the TH-MYCN mice (Fig. 2).…”

Section: Analysis Of Cytogenetic Aberrationsmentioning

confidence: 99%

“…13 We have previously shown a strong correlation between both MYCN and MRP1 expression, 10,[14][15][16] as well as MYCN and ODC gene expression. 17 Human neuroblastoma cell lines have been shown to consist of a mix of different cell types including neuroblastic (N-type) cells, substrate-adherent (S-type) cells and morphologically intermediate (I-type) stem cells that display a capacity for phenotypic interconversion between both N-type and S-type lineages. 18, 19 N-type cells express high levels of neuronal markers including MYCN and tyrosine hydroxylase (TH), while S-type cells appear to be non-tumourigenic cells expressing genetic markers including S100A6 and vimentin.…”

Section: Introductionmentioning

confidence: 99%

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Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

Cheng

Ford

et al. 2007

European Journal of Cancer

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Overexpression of the human MYCN oncogene driven by a tyrosine hydroxylase promoter causes tumours in transgenic mice that recapitulate the childhood cancer neuroblastoma. To establish an in vitro model to study this process, a series of isogenic cell lines were developed from these MYCN-driven murine tumours. Lines were established from tumours arising in homozygous and hemizygous MYCN transgenic mice. Hemizygous tumours gave rise to cell lines growing only in suspension. Homozygous tumours gave rise to similar suspension lines as well as morphologically distinct substrate-adherent lines characteristic of human S-type neuroblastoma cells. FISH analysis demonstrated selective MYCN transgene amplification in cell lines derived from hemizygous mice. Comparative genomic hybridisation (CGH) and fluorescence in situ hybridisation (FISH) analysis confirmed a range of neuroblastoma-associated genetic changes in the various lines, in particular, gain of regions syntenic with human 17q. These isogenic lines together with the transgenic mice thus represent valuable models for investigating the biological characteristics of aggressive neuroblastoma.

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Section: Discussionmentioning

confidence: 97%

Section: Fluorescent Immunocytochemistrymentioning

confidence: 99%

Section: Rna Isolation and Gene Expression Analysismentioning

confidence: 99%

“…6,16,17 FISH analysis was performed to quantify MYCN transgene copy number in tissues and cell lines from the TH-MYCN mice (Fig. 2).…”

Section: Analysis Of Cytogenetic Aberrationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

Cheng

Ford

et al. 2007

European Journal of Cancer

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miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p inhibit tumor progression by directly targeting MYCN in neuroblastoma

et al. 2019

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Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Despite current aggressive treatment regimens, the prognosis for high‐risk NB patients remains poor, with the survival of less than 40%. Amplification/stabilization of MYCN oncogene, in NB is associated with a high risk of recurrence. Thus, there is an urgent need for novel therapeutics. The deregulated expression of microRNA (miR) is reported in NB; nonetheless, its effect on MYCN regulation is poorly understood. First, we identified that miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p (hereafter miR‐15a, miR‐15b or miR‐16) were down‐regulated in patient‐derived xenografts (PDX) with high MYCN expression. MiR targeting sequences on MYCN mRNA were predicted using online databases such as TargetScan and miR database. The R2 database, containing 105 NB patients, showed an inverse correlation between MYCN mRNA and deleted in lymphocytic leukemia (DLEU) 2, a host gene of miR‐15. Moreover, overexpression of miR‐15a, miR‐15b or miR‐16 significantly reduced the levels of MYCN mRNA and N‐Myc protein. Conversely, inhibiting miR dramatically enhanced MYCN mRNA and N‐Myc protein levels, as well as increasing mRNA half‐life in NB cells. By performing immunoprecipitation assays of argonaute‐2 (Ago2), a core component of the RNA‐induced silencing complex, we showed that miR‐15a, miR‐15b and miR‐16 interact with MYCN mRNA. Luciferase reporter assays showed that miR‐15a, miR‐15b and miR‐16 bind with 3’UTR of MYCN mRNA, resulting in MYCN suppression. Moreover, induced expression of miR‐15a, miR‐15b and miR‐16 significantly reduced the proliferation, migration, and invasion of NB cells. Finally, transplanting miR‐15a‐, miR‐15b‐ and miR‐16‐expressing NB cells into NSG mice repressed tumor formation and MYCN expression. These data suggest that miR‐15a, miR‐15b and miR‐16 exert a tumor‐suppressive function in NB by targeting MYCN. Therefore, these miRs could be considered as potential targets for NB treatment.

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Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations

Bosse

Maris

2015

Cancer

189

161

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Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus, which has catalyzed not only a more comprehensive understanding of neuroblastoma tumorigenesis, but has also revealed novel oncogenic vulnerabilities that are being leveraged therapeutically. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN amplification, for risk stratification. Given the relative paucity of recurrent activating somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed towards aberrantly regulated pathways in relapsed disease. This review will summarize the current state of knowledge of neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma.

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Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma

Cited by 95 publications

References 37 publications

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

Cell lines from MYCN transgenic murine tumours reflect the molecular and biological characteristics of human neuroblastoma

miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p inhibit tumor progression by directly targeting MYCN in neuroblastoma

Advances in the translational genomics of neuroblastoma: From improving risk stratification and revealing novel biology to identifying actionable genomic alterations

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