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Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient Diamond-Blackfan anemia improves following RPS19 gene transfer

Hamaguchi, Isao LU ; Flygare, Johan LU ; Nishiura, Hiroshi LU ; Brun, Ann LU ; Ooka, Andreas LU ; Kiefer, Thomas LU ; Ma, Zhi LU ; Dahl, N; Richter, Johan LU and Karlsson, Stefan LU (2003) In Molecular Therapy 7(5). p.613-622
Abstract
Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FIL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic... (More)
Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FIL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
hematopoietic progenitors, lentiviral vectors, gene therapy, Diamond-Blackfan anemia
in
Molecular Therapy
volume
7
issue
5
pages
613 - 622
publisher
Nature Publishing Group
external identifiers
  • pmid:12718904
  • wos:000182645800009
  • scopus:0038190929
ISSN
1525-0024
DOI
10.1016/S1525-0016(03)00091-1
language
English
LU publication?
yes
id
a4771b6c-1150-427f-a70a-c2fe50a441ba (old id 311958)
date added to LUP
2007-09-03 14:22:58
date last changed
2018-10-14 03:32:37
@article{a4771b6c-1150-427f-a70a-c2fe50a441ba,
  abstract     = {Diamond-Blackfan anemia (DBA) is a congenital bone marrow failure syndrome characterized by a specific deficiency in erythroid progenitors. Since some patients with DBA develop a reduction in thrombocytes and granulocytes with age, we asked whether multipotent hematopoietic progenitors from DBA patients had normal proliferative capacity in liquid expansion cultures. CD34(+) cells derived from DBA patients showed deficient proliferation in liquid culture containing IL-3, IL-6, and SCF. Single CD34(+) CD38(-) cells from DBA patients exhibited deficient proliferation recruitment in a limiting dilution assay containing IL-3, IL-6, SCF, Tpo, FIL, and G-CSF or containing IL-3, IL-6, and SCF. Our findings suggest that the underlying hematopoietic defect in DBA may not be limited to the erythroid lineage. Since a fraction of DBA patients have a deficiency in ribosomal protein S19 (RPS19), we constructed lentiviral vectors containing the RPS19 gene for overexpression in hematopoietic progenitors from RPS19-deficient DBA patients. Enforced expression of the RPS19 transgene improved the proliferation of CD34(+) cells from DBA patients with RPS19 mutation. Similarly, enforced expression of RPS19 improved erythroid development of RPS19-deficient hematopoietic progenitors as determined by colony assays and erythroid differentiation cultures. These findings suggest that gene therapy for RPS19-deficient DBA is feasible.},
  author       = {Hamaguchi, Isao and Flygare, Johan and Nishiura, Hiroshi and Brun, Ann and Ooka, Andreas and Kiefer, Thomas and Ma, Zhi and Dahl, N and Richter, Johan and Karlsson, Stefan},
  issn         = {1525-0024},
  keyword      = {hematopoietic progenitors,lentiviral vectors,gene therapy,Diamond-Blackfan anemia},
  language     = {eng},
  number       = {5},
  pages        = {613--622},
  publisher    = {Nature Publishing Group},
  series       = {Molecular Therapy},
  title        = {Proliferation deficiency of multipotent hematopoietic progenitors in ribosomal protein S19 (RPS19)-deficient Diamond-Blackfan anemia improves following RPS19 gene transfer},
  url          = {http://dx.doi.org/10.1016/S1525-0016(03)00091-1},
  volume       = {7},
  year         = {2003},
}