The ribosome-related protein, SBDS, is critical for normal erythropoiesis

Abstract

Although anemia is common in ShwachmanDiamond syndrome (SDS), the underlying mechanism remains unclear. We asked whether SBDS, which is mutated in most SDS patients, is critical for erythroid development. We found that SBDS expression is high early during erythroid differ- IntroductionShwachman-Diamond syndrome (SDS) is a rare multisystem disorder, primarily affecting the bone marrow, pancreas, and skeletal systems. 1,2 Hematologic abnormalities are a major cause for morbidity and mortality and include cytopenia, myelodysplastic syndromes, and leukemia. Neutropenia is observed in almost all SDS patients. Approximately 85% of the patients have hypomorphic mutations in the Shwachman Bodian Diamond syndrome gene, SBDS. 3,4 Knockdown of the SBDS homolog in murine myeloid 32Dcl3 cells resulted in normal neutrophil maturation but reduced viability of granulocyte precursors. 5 These studies provide evidence that SBDS is critical for normal granulopoiesis. The role of SBDS in erythroid development has not been characterized. Anemia is observed in ϳ 60% of SDS patients. In addition, 60% of the patients have high erythrocyte mean corpuscular volume, and 70% have high fetal hemoglobin blood levels. 4,6,7 Despite these erythrocyte abnormalities, SDS has frequently been classified as an inherited neutropenia disorder. 8,9 The underlying mechanism of anemia and the degree to which it can be attributed to erythropoietic failure, nutritional deficiencies, and/or recurrent infection have not been studied.Most SDS bone marrows are hypocellular with reduced hematopoietic progenitors, including erythroid cells. Nevertheless, the defects mediated by SBDS deficiency that are responsible for this phenotype are unclear. For example, it is unknown whether the reduction in SDS hematopoietic progenitors is the result of an impaired ability to differentiate or to proliferate or because of a defect to survive throughout the process of maturation. Previous studies support SBDS roles in several cellular pathways, including cell survival. 10,11 Studies on SDS marrow cells similarly showed reduced hematopoietic stem cells/early progenitors (HSC/Ps) and colony formation. 12 In both SDS marrow cells and SBDSknockdown HeLa cells, the slow cell expansion was in part the result of Fas-mediated apoptosis. 13 Importantly, inhibition of apoptosis in HeLa cells rescued the slow cell expansion phenotype. Elevated levels of reactive oxygen species (ROS) may affect erythroid cell survival and can cause cytopenia. 14, 15 We have previously found that knockdown of SBDS in myeloid and nonmyeloid cell lines causes elevated ROS levels, and balancing ROS levels improved cell survival and expansion. 16 Although these studies shed light on the role of SBDS in cell survival, they were not performed on differentiating cells and may not accurately represent the SBDS role during maturation of hematopoietic cells.A role of SBDS in promoting ribosome biogenesis has also been suggested. [17][18][19][20] The yeast homolog has been shown to play a role in maturation of th...

Marrow failure: a window into ribosome biology

“…[67][68][69] iPSCs derived from SDS patients manifest deficits in exocrine pancreatic and hematopoietic differentiation and enhanced apoptosis. 70 Deletion of murine Sbds resulted in early embryonic lethality.…”

Activation of the mTOR signaling pathway by L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts

“…5,6 Haploinsufficiency of RPS14 in the 5q-syndrome is associated with a block in the processing of pre-ribosomal RNA 4 and deregulation of ribosomal-and translation-related genes. 7 Defective ribosome biogenesis can result in a reduction in the efficiency of mRNA translation 4,8 and cultured erythroblasts from patients with the 5q-syndrome, 8 and the ribosomopathy Schwachman-Diamond syndrome, 9 exhibit impaired mRNA translation. Therefore, this defect in translation may represent a potential therapeutic target in the 5q-syndrome and other ribosomopathies.…”

“…One potential relevant factor is the specific constitutional JAK2 haplotype, designated 46/1 or GGCC, which is correlated with JAK2V617F in cases of European descent. [6][7][8][9] We recently reported that Chinese with PMF have different clinical features than that of Europeans with PMF despite a similar frequency of JAK2V617F. 10 We sought to determine whether the JAK2 46/1 haplotype was also associated with JAK2V617F in Chinese and whether differences in the frequency of this genotype might explain different clinical phenotypes of Chinese and Europeans with PMF and other MPNs.…”

Effects of L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts

“…Colony-forming cell assay was performed on cultured cells from one MDS patient with del(5q) and treatment with L-leucine increased the number of BFU-E colonies (Supplementary Figure 1b). Interestingly, Sen et al 14 have recently shown that treatment with L-leucine resulted in improved BFU-E colony growth in cultured cells from two of the three patients with the ribosomopathy SchwachmanDiamond syndrome.…”