On new and current treatments for Diamond-Blackfan anemia

Research output: ThesisDoctoral Thesis (compilation)


Diamond-Blackfan anemia (DBA) is a rare congenital disease where the patients suffer from macrocytic anemia due to reduced numbers of erythroid precursors in the bone marrow. Most patients carry mutations in ribosomal proteins, such as ribosomal protein S19 (RPS19), which causes deficient ribosome biogenesis and affects protein translation. Ribosomal protein mutations also cause increased apoptosis in erythroid precursors due to upregulation of the tumor suppressor p53 and reduced translation of certain mRNAs important for erythropoiesis. This leads to a reduction of the pool of cells able to differentiate and give rise to red blood cells. DBA patients receive glucocorticoid treatment or blood transfusions to alleviate the anemia, but both treatments have severe side effects which negatively affects the quality of life for the patients. For this reason, it is important to gain deeper understanding of the mechanisms underlying DBA and utilize this knowledge to develop more disease-specific treatments for DBA. Studying mechanisms behind current treatments could provide knowledge needed to develop new therapies. About 40% of all DBA patients receive glucocorticoid treatment, but the disease specific mechanisms behind glucocorticoid treatment in DBA are not fully elucidated. Work presented here identifies that glucocorticoid treatment reduces p53 upregulation and increases the survival and delays differentiation of Rps19 deficient erythroid precursors. In the search for new disease mechanisms behind DBA, we discovered increased levels of unbound intracellular heme in purified Rps19 deficient erythroblasts. To identify of genes able to modify the disease phenotype we performed a custom shRNA based screen for 750 genes hypothesized to affect the DBA phenotype. The screen identified that knock down of the heme-sensing regulator of eukaryotic initiation factor 2a mediated translation (HRI) improved erythroid precursor proliferation in Rps19 deficient mice and reduced both elevated heme levels and decreased the increased p53 activity. A small drug screen identified a1-microglobulin (A1M) to increase proliferation of both Rps19 deficient murine erythroid precursors as well as erythroid percursors from DBA patients by reducing heme levels. Interestingly, A1M treatment did not affect either heme synthesis or p53 activity. Together, these studies show that glucocorticoid treatment decreases p53 activity in Rsp19 deficient erythroid precursors and that elevated heme levels are seen in a mouse model for DBA. Work presented here propose that targeting elevated heme levels in DBA can be used as a new therapeutic strategy.


Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical and Health Sciences


  • Diamond-Blackfan anemia, Erythropoiesis, Ribosome biogenesis, Heme synthesis, Glucocorticoids, p53, Globin translation, HRI, a1-microglobulin
Original languageEnglish
Awarding Institution
Supervisors/Assistant supervisor
Award date2018 Dec 21
Place of PublicationLund
  • Lund University: Faculty of Medicine
Print ISBNs978-91-7619-730-1
Publication statusPublished - 2018
Publication categoryResearch

Bibliographic note

Defence details Date: 2018-12-21 Time: 09:00 Place: Belfragesalen, BMC D15, Klinikgatan 32 i LundExternal reviewer Name: von Lindern, Marieke Title: Associate Professor Affiliation: Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

Total downloads

No data available

Related research output

Sara Sjögren, Kavitha Siva, Shamit Soneji, Amee J George, Marcus Winkler, Pekka Jaako, Marcin Wlodarski, Stefan Karlsson, Ross D Hannan & Johan Flygare, 2015, In: British Journal of Haematology. 171, 4, p. 517-529

Research output: Contribution to journalArticle

View all (1)