Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future.

Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association-dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

NAD+ cleavage activity by animal and plant TIR domains in cell death pathways

The role of the ALK receptor in cancer biology

Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has s...

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Overview and recent advances in the treatment of neuroblastoma

The majority of patients with neuroblastoma have tumors that initially respond to chemotherapy, but a large proportion will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole-genome sequencing of 23 paired diagnostic and relapse neuroblastomas showed clonal evolution from the diagnostic tumor, with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK pathway. Seven of these events were detected only in the relapse tumor, whereas the others showed clonal enrichment. In neuroblastoma cell lines, we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18; 61%), and these lesions predicted sensitivity to MEK inhibition in vitro and in vivo. Our findings provide a rationale for genetic characterization of relapse neuroblastomas and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.

/pdf/relapsed-neuroblastomas-show-frequent-ras-mapk-pathway-16oqhhg8cg.pdf

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

The most economically important diseases of grapevine cultivation worldwide are caused by the fungal pathogen powdery mildew (Erysiphe necator syn Uncinula necator) and the oomycete pathogen downy mildew (Plasmopara viticola) Currently, grapegrowers rely heavily on the use of agrochemicals to minimise the potentially devastating impact of these pathogens on grape yield and quality The wild North American grapevine species Muscadinia rotundifolia was recognised as early as 1889 to be resistant to both powdery and downy mildew We have now mapped resistance to these two mildew pathogens in M rotundifolia to a single locus on chromosome 12 that contains a family of seven TIR-NB-LRR genes We further demonstrate that two highly homologous (86% amino acid identity) members of this gene family confer strong resistance to these unrelated pathogens following genetic transformation into susceptible V vinifera winegrape cultivars These two genes designated Resistance to Uncinula necator (MrRUN1) and Resistance to Plasmopara viticola (MrRPV1) are the first resistance genes to be cloned from a grapevine species Both MrRUN1 and MrRPV1 were found to confer resistance to multiple powdery and downy mildew isolates from France, North America and Australia However, a single powdery mildery isolate collected from the south-eastern region of North America, to which M rotundifolia is native, was capable of breaking MrRUN1-mediated resistance Comparisons of gene organisation and coding sequences between M rotundifolia and the cultivated grapevine V vinifera at the MrRUN1/MrRPV1 locus revealed a high level of synteny suggesting that the TIR-NB-LRR genes at this locus share a common ancestor

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/tpj.12327

Genetic dissection of a TIR-NB-LRR locus from the wild North American grapevine species Muscadinia rotundifolia identifies paralogous genes conferring resistance to major fungal and oomycete pathogens in cultivated grapevine

Nadia Bessoltane Bentahar

Papers

Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Genetic dissection of a TIR-NB-LRR locus from the wild North American grapevine species Muscadinia rotundifolia identifies paralogous genes conferring resistance to major fungal and oomycete pathogens in cultivated grapevine