Neuroblastoma: When differentiation goes awry

Zeineldin, Maged; Patel, Anand G.; Dyer, Michael A.

doi:10.1016/j.neuron.2022.07.012

Cited by 62 publications

(46 citation statements)

References 88 publications

(123 reference statements)

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“…It has been reported that NTRK1, also known as TrkA, could be activated by KLF7 through bind to the endogenous NTRK1 minimal enhancer [25]. Additionally, high NTRK1 expression is a favorable prognostic marker in neuroblastoma and a marker of differentiation [10]. In our study, we con rmed that KLF7-induced neurite outgrowth was accompanied by upregulation of NTRK1 expression (Fig.…”

Section: Klf7 Promotes Neuroblastoma Cell Differentiation Through Reg...supporting

confidence: 73%

“…Accumulated data suggest that a differentiation arrest in sympathoadrenal neuroblasts, which are derived from the neural crest, contributes to the formation of neuroblastoma [6][7][8]. Overcoming differentiation blockage represents a promising strategy for the treatment of high-risk neuroblastoma [9,10]. Currently, only limited strategies for high-risk neuroblastoma differentiation therapy, such as treatment with cis-retinoic acid, have been employed.…”

Section: Introductionmentioning

confidence: 99%

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KLF7 promotes neuroblastoma differentiation through regulation neuroblast differentiation-associated protein AHNAKs and is a marker of clinical outcome

Qiao

Ying

Xie

et al. 2023

Preprint

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Background Recent studies have revealed that neuroblastomas share a close transcriptional similarity with developing adrenal neuroblasts which were often overlooked in previous studies andconfirmed that the neuroblast identity of the neuroblastoma cells. Accumulated data suggest that a differentiation arrest in sympathoadrenal neuroblasts contributes to the formation of neuroblastoma. It has been proposed that KLF7 is a neuroblastoma super-enhancer-associated transcription factor gene. Moreover, KLF7 strongly active in postmitotic neuroblasts of the developing nervous system during embryogenesis. However, the role of KLF7 in the differentiation of neuroblast or neuroblastoma is unknown. Methods Human neuroblastoma cells were used to assess the effects of KLF7 on the proliferation and differentiation biological behaviors of neuroblastoma. CHIP-seq and RNA-seq were used to detect the target gene of KLF7 in neuroblastoma. Luciferase assay, GTPase activity assayand Immunoblotting were utilized to determine the protein–promoter interactions and related molecular mechanisms. Results Firstly, we find a strong association between high KLF7 expression and favorable clinical outcomes in neuroblastoma. Moreover, we find that KLF7 not only inhibits proliferation but also induces differentiation of neuroblastoma cells, surpassing the effects of previously reported neuroblastoma differentiation genes. Furthermore, we are the first one to report that KLF7 binds directly to the promoters of neuroblast differentiation-associated protein (AHNAK and AHNAK2) and regulates their expression to influence the MAPK pathway and GTPase activity and then induces differentiation of neuroblastoma which also indicates that KLF7 plays a crucial role in neuroblast differentiation through regulating neuroblast differentiation-associated protein AHNAKs expression. As reported that KLF7 was a neuroblastoma super-enhancer-associated transcription factor gene, we also observe that depletion of KLF7 in neuroblastoma cells promotes the adrenergic-to-mesenchymal transition, accompanies by changes in enhancer-mediated gene expression. Conclusion we are the first one to report that KLF7 binds directly to the promoters of neuroblast differentiation-associated protein (AHNAK and AHNAK2) and regulates their expression to influence the GTPase activity and then induces differentiation of neuroblastoma which also indicates that KLF7 plays a crucial role in neuroblast differentiation. Our results reveal KLF7 as an inducer of neuroblast or neuroblastoma differentiation with prognostic significance and potential therapeutic value.

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Section: Klf7 Promotes Neuroblastoma Cell Differentiation Through Reg...supporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

KLF7 promotes neuroblastoma differentiation through regulation neuroblast differentiation-associated protein AHNAKs and is a marker of clinical outcome

Qiao

Ying

Xie

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…This implies that gangliosides can be useful stage-specific marker molecules in developing cells, including embryogenesis and stem cells [ 42 ]. NBL cells can differentiate into mature neurons and different stages of differentiation may be present in the same tumor [ 43 ]. Accordingly, we detected a very complex ganglioside profile in neuroblastoma with a mixture of early embryogenesis gangliosides, such as GD2, and gangliosides that are normally present in mature neuronal tissues, such as GD1b and GT1b.…”

Section: Discussionmentioning

confidence: 99%

GD2 Expression in Medulloblastoma and Neuroblastoma for Personalized Immunotherapy: A Matter of Subtype

Paret

Ustjanzew

Ersali

et al. 2022

Cancers

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Neuroblastoma (NBL) and medulloblastoma (MB) are aggressive pediatric cancers which can benefit from therapies targeting gangliosides. Therefore, we compared the ganglioside profile of 9 MB and 14 NBL samples by thin layer chromatography and mass spectrometry. NBL had the highest expression of GD2 (median 0.54 nmol GD2/mg protein), and also expressed complex gangliosides. GD2-low samples expressed GD1a and were more differentiated. MB mainly expressed GD2 (median 0.032 nmol GD2/mg protein) or GM3. Four sonic hedgehog-activated (SHH) as well as one group 4 and one group 3 MBs were GD2-positive. Two group 3 MB samples were GD2-negative but GM3-positive. N-glycolyl neuraminic acid-containing GM3 was neither detected in NBL nor MB by mass spectrometry. Furthermore, a GD2-phenotype predicting two-gene signature (ST8SIA1 and B4GALNT1) was applied to RNA-Seq datasets, including 86 MBs and validated by qRT-PCR. The signature values were decreased in group 3 and wingless-activated (WNT) compared to SHH and group 4 MBs. These results suggest that while NBL is GD2-positive, only some MB patients can benefit from a GD2-directed therapy. The expression of genes involved in the ganglioside synthesis may allow the identification of GD2-positive MBs. Finally, the ganglioside profile may reflect the differentiation status in NBL and could help to define MB subtypes.

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“…Notably, "nervous system development" and "neurogenesis", pathways aberrantly repressed in HR neuroblastoma tumors, were among the most significant biological pathways enriched in bivalent genes and were not present in the top ten most significant biological pathways enriched in H3K27me3-only genes. This suggests that repression of bivalent genes may be involved in preventing the terminal differentiation of neuroblastoma cells into neurons, a critical mechanism involved in the clinical response of HR neuroblastoma tumors to therapy 31 .…”

Section: Bivalent Genes Are Enriched For Mediators Of Differentiation...mentioning

confidence: 99%

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

Chennakesavalu

Moore

Chaves

et al. 2023

Preprint

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Neuroblastoma is the most common extra-cranial solid tumor in childhood and epigenetic dysregulation is a key driver of this embryonal disease. In cell-free DNA from neuroblastoma patients with high-risk disease, we found increased 5-hydroxymethylcytosine (5-hmC) deposition on Polycomb Repressive Complex 2 (PRC2) target genes, a finding previously described in the context of bivalent genes. As bivalent genes, defined as genes bearing both activating (H3K4me3) and repressive (H3K27me3) chromatin modifications, have been shown to play an important role in development and cancer, we investigated the potential role of bivalent genes in maintaining a de-differentiated state in neuroblastoma and their potential use as a biomarker. We identified 313 genes that bore bivalent chromatin marks, were enriched for mediators of neuronal differentiation, and were transcriptionally repressed across a panel of heterogenous neuroblastoma cell lines. Through gene set variance analysis, we developed a clinically implementable bivalent signature. In three distinct clinical cohorts, low bivalent signature was significantly and independently associated with worse clinical outcome in high-risk neuroblastoma patients. Thus, low expression of bivalent genes is a biomarker of ultra-high-risk disease and may represent a therapeutic opportunity in neuroblastoma.

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Neuroblastoma: When differentiation goes awry

Cited by 62 publications

References 88 publications

KLF7 promotes neuroblastoma differentiation through regulation neuroblast differentiation-associated protein AHNAKs and is a marker of clinical outcome

KLF7 promotes neuroblastoma differentiation through regulation neuroblast differentiation-associated protein AHNAKs and is a marker of clinical outcome

GD2 Expression in Medulloblastoma and Neuroblastoma for Personalized Immunotherapy: A Matter of Subtype

5-hydroxymethylcytosine profiling of cell-free DNA identifies bivalent genes that are prognostic of survival in high-risk neuroblastoma

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