Leukaemia‐related gene expression in bone marrow cells from patients with the preleukaemic disorder Shwachman–Diamond syndrome

Rujkijyanont, Piya; Beyene, Joseph; Wei, Kuiru; Khan, Fahad; Dror, Yigal

doi:10.1111/j.1365-2141.2007.06608.x

Cited by 29 publications

(32 citation statements)

References 44 publications

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“…1 Analysis of critical genetic regulators of normal hematopoiesis has identified that constitutional or acquired inactivating mutations of such genes may contribute to bone marrow failure syndromes, myelodysplastic syndromes, and/or hematopoietic neoplasms. [2][3][4] Despite advances in whole-genome analysis, the underlying genetic events that contribute to many hematopoietic disorders remain unclear, and innovative gene-discovery approaches are needed to deepen our understanding of hematopoietic development in order to design more effective and specific therapeutic approaches to treating hematopoietic diseases.In recent years, the zebrafish (Danio rerio) has emerged as an excellent animal model system for studying the genetic pathways of vertebrate development. 5 The combined genetic and embryologic advantages of the zebrafish are ideal for studying organogenesis and, in particular, hematopoiesis.…”

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cpsf1 is required for definitive HSC survival in zebrafish

Bolli

Payne

Rhodes

et al. 2011

Blood

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A comprehensive understanding of the genes and pathways regulating hematopoiesis is needed to identify genes causally related to bone marrow failure syndromes, myelodysplastic syndromes, and hematopoietic neoplasms. To identify novel genes involved in hematopoiesis, we performed an ethyl-nitrosourea mutagenesis screen in zebrafish (Danio rerio) to search for mutants with defective definitive hematopoiesis. We report the recovery and analysis of the grechetto mutant, which harbors an inactivating mutation in cleavage and polyadenylation specificity factor 1 (cpsf1), a gene ubiquitously expressed and required for 3 untranslated region processing of a subset of pre-mRNAs. IntroductionHematopoiesis is a complex developmental process that results in the production of mature blood cells from HSCs and depends on the highly regulated activation of specific genetic programs. 1 Analysis of critical genetic regulators of normal hematopoiesis has identified that constitutional or acquired inactivating mutations of such genes may contribute to bone marrow failure syndromes, myelodysplastic syndromes, and/or hematopoietic neoplasms. [2][3][4] Despite advances in whole-genome analysis, the underlying genetic events that contribute to many hematopoietic disorders remain unclear, and innovative gene-discovery approaches are needed to deepen our understanding of hematopoietic development in order to design more effective and specific therapeutic approaches to treating hematopoietic diseases.In recent years, the zebrafish (Danio rerio) has emerged as an excellent animal model system for studying the genetic pathways of vertebrate development. 5 The combined genetic and embryologic advantages of the zebrafish are ideal for studying organogenesis and, in particular, hematopoiesis. 6 Zebrafish and mammalian hematopoiesis are very comparable with respect to all cell lineages, and key genetic regulators have been conserved through evolution. 7 The sequential waves of zebrafish hematopoietic cell development correspond well with the distinct waves of blood cell generation observed during mammalian embryogenesis. 7 Embryonic hematopoiesis in the zebrafish is divided into 2 major waves that differ in the specific blood cell lineages that are formed. Primitive hematopoiesis is characterized by the generation of embryonic erythrocytes in the intermediate cell mass 8 and a distinct population of primitive macrophages that arise from the anterior lateral plate mesoderm between 14 and 16 hours postfertilization (hpf). 9 Studies in mutants lacking definitive hematopoiesis indicate that most primitive hematopoietic cells are gradually lost between 8 and 12 days postfertilization (dpf). 10 Definitive hematopoiesis occurs in 2 phases: initially, transient erythromyeloid progenitors form in the caudal hematopoietic tissue (CHT) starting around 24 hpf, 11 and by 30 hpf HSCs begin to form in the ventral wall of the dorsal aorta, a region corresponding to the mammalian aorta-gonad-mesonephros region. 12 These HSCs then migrate to the CHT, and from th...

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confidence: 99%

cpsf1 is required for definitive HSC survival in zebrafish

Bolli

Payne

Rhodes

et al. 2011

Blood

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“…Differential expression of genes involved in leukemia, apoptosis, and ribosome biogenesis were reported elsewhere. 10,17,25 All microarray data are available on the Gene Expression Omnibus under accession number GSE32057. …”

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

Sen

Wang

Nghiem

et al. 2011

Blood

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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...

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“…confirmed to be higher in the bone marrow cells of a preleukemia patient, 31) and Tal-1 gene rearrangement has been observed in T-ALL patients. 32) On the basis of this knowledge, we evaluated the possibility of using the Tal-1 gene as a CT antigen candidate.…”

Section: Discussionmentioning

confidence: 75%

“…Spz1 is another bHLH transcription factor, known to be specifically expressed in the testis, that plays a role in the MAPK signaling pathway. 34,35) Tal-1 was expressed in the bone marrow as well as in the developing testis, and expression of it has been reported to be upregulated in pre-leukemic disorder, 31) suggesting that it might be a transcription regulator of commonly activated genes among spermatogenic, bone marrow, and T-ALL cancer stem cells. Several TAL-1 target genes, including tumor suppressor NKX3.1, might participate in T-ALL development.…”

Section: Discussionmentioning

confidence: 99%