A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome

Keersmaecker, Kim De

doi:10.3324/haematol.2015.133777

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…A new generation of dual m-TOR/PI3K inhibitors has been developed, starting from the consideration that the CAT sites of phosphatidylinositol-3-Kinase (PI3K) and m-TOR share a high degree of sequence homology 26 . Neutropenia and myelodysplasia arise from Sbds defects on haematopoietic and osteoprogenitor cells respectively 48 , therefore correction of hyper-activation of JAK/STAT/mTOR pathways is expected to correct both deficiencies. In conclusion, despite the fact that the precise molecular mechanism/s linking SBDS protein to ERK1/2 activation remain obscure and will represent a future subject of investigation, our findings open a wider therapeutic scenario within SDS pathology, providing a new rationale to promote the evaluation of drugs targeting mTOR pathway in SDS patients with the aim to reduce the risk to progression to bone marrow failure, myelodysplasia and leukemic transformation thus avoiding or postponing the need of bone marrow transplantation.…”

Section: Discussionmentioning

confidence: 99%

New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes

Bezzerri

Vella

Calcaterra

et al. 2016

Sci Rep

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Shwachman-Diamond syndrome (SDS) is an inherited disease caused by mutations of a gene encoding for SBDS protein. So far little is known about SBDS exact function. SDS patients present several hematological disorders, including neutropenia and myelodysplastic syndrome (MDS), with increased risk of leukemic evolution. So far, the molecular mechanisms that underlie neutropenia, MDS and AML in SDS patients have been poorly investigated. STAT3 is a key regulator of several cellular processes including survival, differentiation and malignant transformation. Moreover, STAT3 has been reported to regulate neutrophil granulogenesis and to induce several kinds of leukemia and lymphoma. STAT3 activation is known to be regulated by mTOR, which in turn plays an important role in cellular growth and tumorigenesis. Here we show for the first time, to the best of our knowledge, that both EBV-immortalized B cells and primary leukocytes obtained from SDS patients present a constitutive hyper-activation of mTOR and STAT3 pathways. Interestingly, loss of SBDS expression is associated with this process. Importantly, rapamycin, a well-known mTOR inhibitor, is able to reduce STAT3 phosphorylation to basal levels in our experimental model. A novel therapeutic hypothesis targeting mTOR/STAT3 should represent a significant step forward into the SDS clinical practice.

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Section: Discussionmentioning

confidence: 99%

New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes

Bezzerri

Vella

Calcaterra

et al. 2016

Sci Rep

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“…Hence, deregulation of RPs impairs the synthesis, processing and assembly of rRNA, translation and modification of proteins, and eventually lead to the progression of diseases ( Table 3 ) including developmental, systemic and metabolic complications, and cancers [ 24 , 62 , 63 , 64 , 65 , 66 ]. The diseases that are derived from the structural and functional defects of the RPs or rRNA genes or the genes in which products are involved in the assembly and biogenesis of ribosomes are defined by the term ribosomopathy [ 67 , 68 , 69 ]. The diseases that come under the term ribosomopathy include Diamond-Blackfan anemia (DBA), 5q-syndrome, Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DC), cartilage hair hypoplasia (CHH), Treacher Collins syndrome (TCS), Bowen-Conradi syndrome (BCS), North American Indian childhood cirrhosis (NAIC) [ 67 ].…”

Section: Rps Mediated Regulation Of Biological Processes and Progrmentioning

confidence: 99%

microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins

Reza

Yuan

2021

Cells

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Ribosomal proteins (RPs) are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases, and are important structural components of the ribosome, which is a supramolecular ribonucleoprotein complex, composed of Ribosomal RNA (rRNA) and RPs, coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors. Not all RPs are indispensable; in other words, the ribosome could be functional and could continue the translation of proteins instead of lacking in some of the RPs. However, the lack of many RPs could result in severe defects in the biogenesis of ribosomes, which could directly influence the overall translation processes and global expression of the proteins leading to the emergence of different diseases including cancer. While microRNAs (miRNAs) are small non-coding RNAs and one of the potent regulators of the post-transcriptional gene expression, miRNAs regulate gene expression by targeting the 3′ untranslated region and/or coding region of the messenger RNAs (mRNAs), and by interacting with the 5′ untranslated region, and eventually finetune the expression of approximately one-third of all mammalian genes. Herein, we highlighted the significance of miRNAs mediated regulation of RPs coding mRNAs in the global protein translation.

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Shwachman-Diamond syndrome: diagnosis, pathogenesis and prognosis

Valli

Frattini

Minelli

2017

Expert Opinion on Orphan Drugs

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Introduction: Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive disease due to\ud mutations in the SBDS and DNAJC21 genes, both involved in ribosome biogenesis. Patients affected\ud by SDS show widely variable clinical features and have an increased risk to develop myelodysplastic\ud syndrome, aplastic anemia and acute myeloid leukemia.\ud Areas covered: Clinical features from diagnosis to surveillance and treatment of SDS patients are\ud presented. It is mainly addressed the necessity to monitor the haematological and cytogenetic picture\ud of the bone marrow in order to early identify any possible dysplastic/neoplastic sign to quickly treat the\ud condition. Since, hematopoietic stem cell transplant is the only therapy for hematological complications,\ud the useful preparative regimens is extensively discussed. In addition, recent molecular and\ud cytogenetic studies are reported.\ud Expert opinion: In our opinion, due to high variability of pathological phenotype presented by SDS\ud patients, a prompt molecular diagnosis may help the management of the disease and may aim the\ud cytological monitoring at bone marrow level, which could improve the surveillance of patients and, if\ud necessary, carry to a prompt hematopoietic stem cell transplant

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A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome

Cited by 3 publications

References 20 publications

New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes

New insights into the Shwachman-Diamond Syndrome-related haematological disorder: hyper-activation of mTOR and STAT3 in leukocytes

microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins

Shwachman-Diamond syndrome: diagnosis, pathogenesis and prognosis

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