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

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 mM 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.

Mutations in the Heme Exporter FLVCR1 Cause Sensory Neurodegeneration with Loss of Pain Perception

“…In order to demonstrate that increased apoptosis in patient cells treated with ALA was due to heme overload, we performed rescue experiments by reducing intracellular heme loading. It has been previously reported that Hemopexin (HX) facilitates heme export through FLVCR1[31, 32]. Thus, we added HX to the medium.…”

Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors

“…Delayed expression of globin genes in primary DBA cells has been reported to lead to accumulation of free heme and heme toxicity, which perturbs erythroid differentiation (26). We show that knockdown of RPS19 in CD34 + progenitors rapidly inhibited expression of globin transcripts.…”

Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

“…Yang et al in an elegant study showed that disruption of ribosomal assembly as a result of RPS14 haploinsufficiency slows protein synthesis and impairs globin production relative to heme production. This discordant production rate results in excess heme in erythroid colony‐forming units (CFU‐E)/proerythroblasts with consequent excessive generation of reactive oxygen species (ROS), leading to cell death as well as early termination of erythropoiesis by decreasing GATA1 and impeding mitosis . In further support of this mechanism, these investigators showed that once heme synthesis was impaired by restricting iron availability or by facilitating excess heme export through feline leukemia virus subgroup C receptor (FLVCR), erythropoiesis was improved .…”

“…This discordant production rate results in excess heme in erythroid colony‐forming units (CFU‐E)/proerythroblasts with consequent excessive generation of reactive oxygen species (ROS), leading to cell death as well as early termination of erythropoiesis by decreasing GATA1 and impeding mitosis . In further support of this mechanism, these investigators showed that once heme synthesis was impaired by restricting iron availability or by facilitating excess heme export through feline leukemia virus subgroup C receptor (FLVCR), erythropoiesis was improved . Transfusion‐dependent anemia is a significant aspect of del(5q) MDS morbidity that impacts quality of life, and these breakthroughs elucidating the molecular pathogenesis have ushered in investigational therapies that may restore effective erythropoiesis and improve the patient's quality of life.…”