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Bone marrow transplantation without myeloablative conditioning in a mouse model for Diamond-Blackfan anemia corrects the disease phenotype

Dahl, Maria LU ; Warsi, Sarah LU ; Liu, Yang LU ; Debnath, Shubhranshu LU ; Billing, Matilda LU ; Siva, Kavitha LU ; Flygare, Johan LU and Karlsson, Stefan LU orcid (2021) In Experimental Hematology 99. p.2-53
Abstract

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes coding for ribosomal proteins. Among these genes, the ribosomal protein S19 (RPS19) gene is the most frequently mutated. Previously, a mouse model deficient in RPS19 was developed by our laboratory, which recapitulates the hematopoietic disease phenotype by manifesting pathologic features and clinical symptoms of DBA. Characterization of this model revealed that chronic RPS19 deficiency leads to exhaustion of hematopoietic stem cells and subsequent bone marrow (BM) failure. In this study, we evaluated a nonmyeloablative conditioning protocol for BM transplants in RPS19-deficient mice by transplanting wild-type BM cells... (More)

Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes coding for ribosomal proteins. Among these genes, the ribosomal protein S19 (RPS19) gene is the most frequently mutated. Previously, a mouse model deficient in RPS19 was developed by our laboratory, which recapitulates the hematopoietic disease phenotype by manifesting pathologic features and clinical symptoms of DBA. Characterization of this model revealed that chronic RPS19 deficiency leads to exhaustion of hematopoietic stem cells and subsequent bone marrow (BM) failure. In this study, we evaluated a nonmyeloablative conditioning protocol for BM transplants in RPS19-deficient mice by transplanting wild-type BM cells to RPS19-deficient recipients given no conditioning or sublethal doses of irradiation before transplant. We describe full correction of the hematopoietic phenotype in mice given sublethal doses of irradiation, as well as in animals completely devoid of any preceding irradiation. In comparison, wild-type animals receiving the same preconditioning regimen and number of transplanted cells exhibited significantly lower engraftment levels. Thus, robust engraftment and repopulation of transplanted cells can be achieved in reduced-intensity conditioned RPS19-deficient recipients. As gene therapy studies with autologous gene-corrected hematopoietic stem cells are emerging, we propose the results described here can guide determination of the level of conditioning for such a protocol in RPS19-deficient DBA. On the basis of our findings, a relatively mild conditioning strategy would plausibly be sufficient to achieve sufficient levels of engraftment and clinical success.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Experimental Hematology
volume
99
pages
2 - 53
publisher
Elsevier
external identifiers
  • pmid:34126174
  • scopus:85108959315
ISSN
0301-472X
DOI
10.1016/j.exphem.2021.06.002
language
English
LU publication?
yes
id
d3046c6e-fed1-4a36-8d3a-dcee8a033b28
date added to LUP
2021-08-19 11:17:00
date last changed
2024-06-15 14:44:12
@article{d3046c6e-fed1-4a36-8d3a-dcee8a033b28,
  abstract     = {{<p>Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes coding for ribosomal proteins. Among these genes, the ribosomal protein S19 (RPS19) gene is the most frequently mutated. Previously, a mouse model deficient in RPS19 was developed by our laboratory, which recapitulates the hematopoietic disease phenotype by manifesting pathologic features and clinical symptoms of DBA. Characterization of this model revealed that chronic RPS19 deficiency leads to exhaustion of hematopoietic stem cells and subsequent bone marrow (BM) failure. In this study, we evaluated a nonmyeloablative conditioning protocol for BM transplants in RPS19-deficient mice by transplanting wild-type BM cells to RPS19-deficient recipients given no conditioning or sublethal doses of irradiation before transplant. We describe full correction of the hematopoietic phenotype in mice given sublethal doses of irradiation, as well as in animals completely devoid of any preceding irradiation. In comparison, wild-type animals receiving the same preconditioning regimen and number of transplanted cells exhibited significantly lower engraftment levels. Thus, robust engraftment and repopulation of transplanted cells can be achieved in reduced-intensity conditioned RPS19-deficient recipients. As gene therapy studies with autologous gene-corrected hematopoietic stem cells are emerging, we propose the results described here can guide determination of the level of conditioning for such a protocol in RPS19-deficient DBA. On the basis of our findings, a relatively mild conditioning strategy would plausibly be sufficient to achieve sufficient levels of engraftment and clinical success.</p>}},
  author       = {{Dahl, Maria and Warsi, Sarah and Liu, Yang and Debnath, Shubhranshu and Billing, Matilda and Siva, Kavitha and Flygare, Johan and Karlsson, Stefan}},
  issn         = {{0301-472X}},
  language     = {{eng}},
  pages        = {{2--53}},
  publisher    = {{Elsevier}},
  series       = {{Experimental Hematology}},
  title        = {{Bone marrow transplantation without myeloablative conditioning in a mouse model for Diamond-Blackfan anemia corrects the disease phenotype}},
  url          = {{http://dx.doi.org/10.1016/j.exphem.2021.06.002}},
  doi          = {{10.1016/j.exphem.2021.06.002}},
  volume       = {{99}},
  year         = {{2021}},
}