title: Glucocorticoids improve erythroid progenitor maintenance and dampen Trp53 response in a mouse model of Diamond-Blackfan anaemia.
abstract: Diamond-Blackfan anaemia (DBA) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all DBA patients receive glucocorticoids to alleviate their anaemia. However, despite their use in DBA treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 (Rps19) deficient mouse model of DBA. This study determines for the first time that a mouse model of DBA can respond to glucocorticoid treatment, similar to DBA patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent Trp53 activation in Rps19-deficient cells- in a disease-specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of DBA provides indispensible insight into DBA pathogenesis. Identifying mechanisms important for DBA treatment also enables development of more disease-specific treatments of DBA.
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.|Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Sara E
authors: SE
authors: Sjögren
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.|Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Kavitha
authors: K
authors: Siva
authors: Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Shamit
authors: S
authors: Soneji
authors: Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.|Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors: Amee J
authors: AJ
authors: George
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.|Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Marcus
authors: M
authors: Winkler
authors: Lund Stem Cell Centre, Lund University, Lund, Sweden.|Division of Molecular Haematology, Lund University, Lund, Sweden.
authors: Pekka
authors: P
authors: Jaako
authors: Division of Paediatric Haematology and Oncology, University of Freiburg, Freiburg, Germany.
authors: Marcin
authors: M
authors: Wlodarski
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.|Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Stefan
authors: S
authors: Karlsson
authors: Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, East Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.|Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors: Ross D
authors: RD
authors: Hannan
authors: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.|Lund Stem Cell Centre, Lund University, Lund, Sweden.
authors: Johan
authors: J
authors: Flygare
mesh_terms: D000293:Adolescent; D029503:Anemia, Diamond-Blackfan / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera; D012269:Ribosomal Proteins / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: C494827:Bax protein, mouse; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012269:Ribosomal Proteins; C531064:Rps19 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C091750:ZFP36L2 protein, human; D051028:bcl-2-Associated X Protein; D003907:Dexamethasone; D011239:Prednisolone
keywords: Diamond-Blackfan anaemia; Trp53; erythroid differentiation; erythroid progenitor; glucocorticoid therapy