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Shwachman−Diamond Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
As SBDS encodes a protein involved in ribosome biogenesis, SDS can be considered a ribosomopathy. Being highly evolutionarily conserved organelles, ribosomes are assembled from four types of ribosomal RNAs (rRNA) and about 80 ribosomal proteins (RP), and involved in protein synthesis. Disruption of ribosomal biogenesis by extracellular or intracellular stimuli contributes to ribosomal stress and accumulation of unincorporated/free RP, which bind to and inhibit MDM2 and impair its ubiquitin-mediated degradation of TP53 tumor suppressor, leading to the development of so-called ribosomopathies (characterized by early onset bone marrow failure, variable developmental abnormalities, and a lifelong cancer predisposition) [3–5].
GATA1 insufficiencies in primary myelofibrosis and other hematopoietic disorders: consequences for therapy
Published in Expert Review of Hematology, 2018
Te Ling, John D. Crispino, Maria Zingariello, Fabrizio Martelli, Anna Rita Migliaccio
Hypomorphic Gata1low mice models, obtained either by directly by deleting the regulatory regions of the gene or indirectly by generating mice carrying driver mutations that induce a ribosomopathy that impairs Gata1 mRNA translation, are playing an important role in identifying possible molecular targets to cure human PMF. The observation that Gata1low mice express an activated TPO/JAK2 pathway led us to investigate the effects of ruxolitinib, a JAK inhibitor approved by the US FDA for clinical use in PMF in this model. Similar to the effects exerted on the patients [115], treatment with ruxolitinib at doses similar to those used in Jak2V617F animal models [116] greatly reduced spleen size but had modest effects on bone marrow hematopoiesis, suggesting that this drug may be more efficacious when used in combination with other drugs targeting the malignant HSC or their microenvironment.
Hematopoietic stem cell transplantation for classical inherited bone marrow failure syndromes: an update
Published in Expert Review of Hematology, 2021
Filomena Pierri, Maura Faraci, Stefano Giardino, Carlo Dufour
DBA is a rare (6–7 per million live births) IBMFS characterized by hypoplastic anemia, congenital anomalies, and a predisposition to malignancies (AML/MDS and solid tumors such as osteosarcoma, colon cancer) [62]. The majority of patients with DBA carry haploinsufficient mutations in one of the 23 genes known so far to cause the disease. The vast majority of these genes are involved in ribosomogenesis; hence, DBA is a ‘ribosomopathy’ [63]. Although the advent of new genetic tools has reduced the number of patients in whom a pathogenic mutation has not been found, in about 20% of patients there is no causative gene [64].