Hematopoietic stem/progenitor cell transplantation recovers immune defects and prevents lymphomas in Atm-deficient mice.
ATM
Genomic stability
HSPCT
Lymphomas
T and B cells
Journal
Experimental hematology & oncology
ISSN: 2162-3619
Titre abrégé: Exp Hematol Oncol
Pays: England
ID NLM: 101590676
Informations de publication
Date de publication:
06 Aug 2024
06 Aug 2024
Historique:
received:
30
10
2023
accepted:
24
07
2024
medline:
7
8
2024
pubmed:
7
8
2024
entrez:
6
8
2024
Statut:
epublish
Résumé
Ataxia-telangiectasia (A-T) is a rare autosomal recessive multi-system and life-shortening disease, characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition, with high incidence of leukemia and lymphoma. A-T is caused by mutations in the gene encoding for ATM protein that has a major role in maintaining the integrity of the genome. Because there are no cures for A-T, we aimed to tackle immunodeficiency and prevent cancer onset/progression by transplantation therapy. Enriched hematopoietic stem/progenitor cells (HSPCs), collected from bone marrow of wild-type mice, were transplanted in the caudal vein of 1 month old conditioned Atm Genomic analyses showed that transplanted Atm positive cells were found in lymphoid organs. B cells isolated from spleen of transplanted mice were able to undergo class switching recombination. Thymocytes were capable to correctly differentiate and consequently an increase of helper T cells and TCRβ We can conclude that wild-type enriched HSPCs transplantation into young Atm-deficient mice can ameliorate A-T hematopoietic phenotypes and prevent tumor of hematopoietic origin.
Sections du résumé
BACKGROUND
BACKGROUND
Ataxia-telangiectasia (A-T) is a rare autosomal recessive multi-system and life-shortening disease, characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiation sensitivity and cancer predisposition, with high incidence of leukemia and lymphoma. A-T is caused by mutations in the gene encoding for ATM protein that has a major role in maintaining the integrity of the genome. Because there are no cures for A-T, we aimed to tackle immunodeficiency and prevent cancer onset/progression by transplantation therapy.
METHODS
METHODS
Enriched hematopoietic stem/progenitor cells (HSPCs), collected from bone marrow of wild-type mice, were transplanted in the caudal vein of 1 month old conditioned Atm
RESULTS
RESULTS
Genomic analyses showed that transplanted Atm positive cells were found in lymphoid organs. B cells isolated from spleen of transplanted mice were able to undergo class switching recombination. Thymocytes were capable to correctly differentiate and consequently an increase of helper T cells and TCRβ
CONCLUSION
CONCLUSIONS
We can conclude that wild-type enriched HSPCs transplantation into young Atm-deficient mice can ameliorate A-T hematopoietic phenotypes and prevent tumor of hematopoietic origin.
Identifiants
pubmed: 39107850
doi: 10.1186/s40164-024-00544-0
pii: 10.1186/s40164-024-00544-0
doi:
Types de publication
Letter
Langues
eng
Pagination
81Subventions
Organisme : AIRC 2019
ID : AIRC 2019 [IG 23329]
Organisme : ANAT
ID : ANAT2019
Organisme : FESR Lazio Innova
ID : POR 2014-2020- A0375-2020-36524
Informations de copyright
© 2024. The Author(s).
Références
Shiloh Y. ATM and related protein kinases: Safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155–68.
doi: 10.1038/nrc1011
pubmed: 12612651
Reina-San-Martin B, Chen HT, Nussenzweig A, Nussenzweig MC. ATM is required for efficient recombination between immunoglobulin switch regions. J Exp Med. 2004;200(9):1103–10.
doi: 10.1084/jem.20041162
pubmed: 15520243
pmcid: 2211855
Bakhtiar S, Salzmann-Manrique E, Donath H, Woelke S, Duecker RP, Fritzemeyer S, et al. The incidence and type of cancer in patients with ataxia-telangiectasia via a retrospective single-centre study. Br J Haematol. 2021;194(5):879–87.
doi: 10.1111/bjh.17736
pubmed: 34337741
Bowen S, Wangsa D, Ried T, Livak F, Hodes RJ. Concurrent V(D)J recombination and DNA end instability increase interchromosomal trans-rearrangements in ATM-deficient thymocytes. Nucleic Acids Res. 2013;41(8):4535–48.
doi: 10.1093/nar/gkt154
pubmed: 23470994
pmcid: 3632137
Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis. 2016;11(1):1–21.
doi: 10.1186/s13023-016-0543-7
Lavin MF, Gueven N, Bottle S, Gatti RA. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull. 2007;81–82(1):129–47.
doi: 10.1093/bmb/ldm012
pubmed: 17586848
van Os NJH, Haaxma CA, van der Flier M, Merkus PJFM, van Deuren M, de Groot IJM, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol. 2017;59(7):680–9.
doi: 10.1111/dmcn.13424
pubmed: 28318010
de Oliveira BSP, Putti S, Naro F, Pellegrini M. Bone marrow transplantation as therapy for ataxia-telangiectasia: a systematic review. Cancers. 2020;12(11):1–12.
Pai SY, Notarangelo LD. Congenital disorders of lymphocyte function. 7th ed. Amsterdam: Hematology Basic Principles and Practice. Elsevier Inc; 2018. p. 710–23.
Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell. 1996;86(1):159–71.
doi: 10.1016/S0092-8674(00)80086-0
pubmed: 8689683
Bagley J, Cortes ML, Breakefield XO, Iacomini J. Bone marrow transplantation restores immune system function and prevents lymphoma in Atm-deficient mice. Blood. 2004;104(2):572–8.
doi: 10.1182/blood-2003-12-4226
pubmed: 15044255
Pietzner J, Baer PC, Duecker RP, Merscher MB, Satzger-prodinger C, Bechmann I, et al. Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of Atm-competent cells. Hum Mol Genet. 2013;22(3):493–507.
doi: 10.1093/hmg/dds448
pubmed: 23100326
Duecker RP, Gronau L, Baer PC, Zielen S, Schubert R. Stem cell transplantation in ATM- deficient Mice. Front Immunol. 2021;29(12): 693897.
doi: 10.3389/fimmu.2021.693897
Di Siena S, Campolo F, Gimmelli R, Di Pietro C, Marazziti D, Dolci S, Lenzi A, Nussenzweig A, Pellegrini M. Atm reactivation reverses ataxia telangiectasia phenotypes in vivo. Cell Death Dis. 2018;9(3):314.
doi: 10.1038/s41419-018-0357-8
pubmed: 29472706
pmcid: 5833483
Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T. In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood. 1992;80(12):3044–50.
doi: 10.1182/blood.V80.12.3044.3044
pubmed: 1281687