Research ArticleGenetics

Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome

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Science Translational Medicine  11 May 2016:
Vol. 8, Issue 338, pp. 338ra67
DOI: 10.1126/scitranslmed.aaf3006

Putting the heme in anemia

Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) are both associated with impaired ribosome assembly; however, how the ribosomal defect connects to anemia remains unknown. Yang et al. report that ribosomal deficiencies in individuals with either DBA or Del(5q) MDS lead to insufficient globin protein synthesis but normal heme synthesis, which results in excess heme and reactive oxygen species in early erythroid precursors and proerythroblast cell death. Treating affected cells with an inhibitor of heme synthesis improves erythroid cell output in cell culture. Thus, blocking heme synthesis may serve as a therapeutic strategy in individuals with DBA or Del(5q) MDS.


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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