Ribosomopathies: New Therapeutic Perspectives

Orgebin, Emilien; Lamoureux, François; Isidor, Bertrand; Charrier, Céline; Ory, Benjamin; Lezot, Frédéric; Baud’huin, Marc

doi:10.3390/cells9092080

Cited by 24 publications

(17 citation statements)

References 146 publications

(167 reference statements)

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“…This includes chronic blood transfusions followed by steroids to allow patients to survive this disease phase (Table 2), but with many undesirable and even fatal side effects after long-term of steroids, including hypertension, diabetes mellitus, and growth retardation. 257 There is clearly an unmet need in developing new therapeutic strategies for ribosomopathies.…”

Section: The Molecular Basis Of Ribosomopathiesmentioning

confidence: 99%

Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Kang

Brajanovski

Chan

et al. 2021

Sig Transduct Target Ther

195

127

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Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed “Dameshek’s riddle.” Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. We also highlight recent advances in ribosome stress-based cancer therapeutics. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.

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Section: The Molecular Basis Of Ribosomopathiesmentioning

confidence: 99%

Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Kang

Brajanovski

Chan

et al. 2021

Sig Transduct Target Ther

195

127

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“…L-leucine, a branch chain amino acid, is a potential emerging treatment for DBA, and other ribosomopathies, that upregulates ribosome biosynthesis via the mTOR signaling pathway and targets the underlying RP dysfunction ( Payne et al, 2012 ; Xu et al, 2016 ; Orgebin et al, 2020 ). In a recent study, L-leucine treatment resulted in erythroid responses in a small number of transfusion-dependent patients with DBA, and improved weight gain and linear growth velocity in a larger number of patients ( Vlachos et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19

et al. 2022

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Introduction:Diamond Blackfan anemia (DBA) is an autosomal dominant ribosomopathy caused predominantly by pathogenic germline variants in ribosomal protein genes. It is characterized by failure of red blood cell production, and common features include congenital malformations and cancer predisposition. Mainstays of treatment are corticosteroids, red blood cell transfusions, and hematologic stem cell transplantation (HSCT). Despite a better understanding of the genotype of DBA, the biological mechanism resulting in the clinical phenotype remains poorly understood, and wide heterogeneity can be seen even within a single family as depicted here.Case Description:Thirty family members enrolled in the National Cancer Institute inherited bone marrow failure syndromes study were evaluated with detailed medical questionnaires and physical examinations, including 22 in the family bloodline and eight unrelated partners. Eight participants had been previously told they had DBA by clinical criteria. Targeted germlineRPS19testing was done on all family members. A pathogenic heterozygous missense mutation inRPS19(p.R62Q, c.185G > A) was detected in ten family members, including one person previously presumed unaffected. Eight family members presented with macrocytic anemia in infancy; all of whom were responsive to prednisone. Four family members became treatment independent; however, one individual became transfusion-dependent 36 years later following an episode of pneumonia. One prednisone responsive individual electively discontinued steroid treatment, and lives with severe anemia. One prednisone responsive individual died at age 28 from a stroke. Two family members developed colorectal cancer in their fifties; one had never required treatment for anemia. None had major congenital anomalies.Discussion:This large family with DBA demonstrates the heterogeneity of phenotypes that can be seen within the same genotype. Most family members presented with steroid-responsive anemia in infancy and subtle congenital malformations, findings consistent with recent genotype-phenotype studies ofRPSDBA. However, two family members were relatively unaffected, underscoring the importance of further studies to assess modifier genes, and epigenetic and/or environmental factors which may result in normal erythropoiesis despite underlying ribosome dysfunction. This large, multigenerational family highlights the need for individualized treatment, the importance of early cancer surveillance even in individuals with clinically mild phenotypes, and the benefit of long-term follow-up to identify late complications.

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“…Ribosomes are comprised of ribonucleoprotein and non-coding ribosomal RNAs in eukaryotes and are conserved molecular structures required for protein synthesis [26]. Cancer development and progression are associated with ribosomal dysregulation, which affects the expression of key factors involved in tumorigenesis [27]. It has been reported that a single ribosomal assembly factor promotes LUAD progression through the Notch signaling pathway [28].…”

Section: Discussionmentioning

confidence: 99%

The Role of SRMS in Colorectal Cancer by Bioinformatics Analysis

Zhang¹,

Liu²,

Feng³

et al. 2021

Preprint

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Background:Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (SRMS) is a non-receptor tyrosine kinase that has been found to be overexpressed in various tumors. Therefore, it may be an important carcinogenic factor whose role in colorectal cancer (CRC) has not been established. Methods: We evaluated the expression patterns of SRMS in CRC using GEPIA, Oncomine and HPA datasets while the association between SRMS and clinicopathological features was analyzed using a UALCAN dataset. LinkedOmics was used to determine co-expression and functional networks associated with SRMS. Besides, we used TISIDB to assess the correlation between SRMS and immune signatures, including tumor-infiltrating immune cells and immunomodulators. Lastly, protein-protein interaction network establishment and pathway enrichment analysis of the SRMS-associated 33 immunomodulators and 191 immune cell marker genes were performed using the STRING portal. Results: Compared to normal colorectal tissues, SRMS was found to be upregulated in CRC tissues, and was correlated with higher pathological stages and nodal metastasis status. Functional network analysis suggested that SRMS regulates intermediate filament-based processes, protein autophosphorylation, translational initiation and elongation signaling through pathways involving ribosomes, proteasomes, oxidative phosphorylation, and DNA replication. In addition, SRMS expression was correlated with infiltrating levels of CD4+ T cells, CD56dim, MEM B, Neutrophils, Th2, Th17, and Act DC. Pathway enrichment analysis of SRMS-associated 33 immunomodulators and 191 immune cell marker genes indicated that they are involved multiple cancer-related pathways. Conclusions: SRMS is a promising prognostic biomarker and a potential therapeutic target for CRC patients. In particular, SRMS regulates CRC progression by modulating chemokines, IL-17, intestinal immune networks for IgA production, and cytokine-cytokine receptor interaction signaling pathways among others. However, more studies are needed to validate these findings.

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Ribosomopathies: New Therapeutic Perspectives

Cited by 24 publications

References 146 publications

Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19

The Role of SRMS in Colorectal Cancer by Bioinformatics Analysis

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