AI Article Synopsis

  • Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are serious types of anemia linked to problems with ribosome assembly, but the exact cause of the anemia is unclear.
  • Research on patient marrow cells shows that the translation of globin protein is slow, while heme synthesis is normal, leading to an imbalance that causes cell death in early erythroid precursors.
  • Treatment with succinylacetone, a heme synthesis inhibitor, significantly improved red blood cell production in DBA and del(5q) MDS cultures, indicating that managing heme levels could be key in treating these anemias.

Article Abstract

Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010382PMC
http://dx.doi.org/10.1126/scitranslmed.aaf3006DOI Listing

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