Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential

Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, multilineage hematopoietic dysfunction, and metaphyseal chondrodysplasia. Bone marrow dysfunction is present in nearly all patients with SDS, with neutropenia being the most common abn...

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Bibliographic Details
Published in:Blood 2007-10, Vol.110 (7), p.2414-2422
Main Authors: Rawls, Amy S., Gregory, Alyssa D., Woloszynek, Jill R., Liu, Fulu, Link, Daniel C.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - cytology
B-Lymphocytes - metabolism
Base Sequence
Biological and medical sciences
Bone Marrow Transplantation
Cell Differentiation
Cell Movement
Cells, Cultured
Gene Expression Regulation
Granulocytes - cytology
Granulocytes - metabolism
Hematologic and hematopoietic diseases
Hematopoiesis
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Lentivirus - genetics
Medical sciences
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Myeloid Cells - cytology
Myeloid Cells - metabolism
Proteins - genetics
Proteins - metabolism
RNA Interference
Time Factors
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Summary:Shwachman-Diamond syndrome (SDS) is a rare multisystem disorder characterized by exocrine pancreatic insufficiency, multilineage hematopoietic dysfunction, and metaphyseal chondrodysplasia. Bone marrow dysfunction is present in nearly all patients with SDS, with neutropenia being the most common abnormality. The majority of patients with SDS have mutations in the Shwachman Bodian Diamond syndrome (SBDS) gene. We have developed a strategy to examine the consequences of lentiviral-mediated RNA interference (RNAi) of Sbds on hematopoiesis. Here, we report that both Sbds RNA and protein expression can be efficiently inhibited in primary murine hematopoietic cells using lentiviral-mediated RNAi. Inhibition of Sbds results in a defect in granulocytic differentiation in vitro and impairs myeloid progenitor generation in vivo. In addition, short-term hematopoietic engraftment was impaired, which is due in part to reduced homing of hematopoietic progenitors to the bone marrow. Finally, we show that inhibition of Sbds is associated with a decrease in circulating B lymphocytes, despite evidence of normal B lymphopoiesis. These data provide the first evidence that loss of Sbds is sufficient to induce abnormalities in hematopoiesis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2006-03-007112