The production of two components of hemoglobin may be out of sync in Diamond Blackfan anemia (DBA) and myelodysplastic syndromes (MDS), according to a new study.
Researchers found that, in samples from patients with DBA or MDS, ribosome dysfunction delayed globin production, while heme synthesis proceeded normally.
This disruption in heme-globin coordination led to a buildup of toxic heme that killed red blood cell (RBC) precursors.
However, treating patient samples with a compound that blocks heme synthesis increased RBC production in both DBA and MDS.
Zhantao Yang, MD, of the University of Washington in Seattle, and his colleagues reported these findings in Science Translational Medicine.
Both DBA and MDS have been linked to defects in ribosome assembly, which is critical to protein production, but how this leads to anemia remains unknown.
To find out, Dr Yang and his colleagues analyzed bone marrow cells from patients with DBA (n=3) or MDS with del(5q) (n=6).
The researchers found that globin translation proceeded slowly in these samples, but heme synthesis proceeded normally.
This resulted in insufficient globin, excess heme, and excess reactive oxygen species in early erythroid precursors and, ultimately, the death of colony-forming unit–erythroid/proerythroblast cells.
The cells that were able to rapidly export heme or slow its synthesis survived and matured into RBCs, but the other colony-forming unit–erythroid cells/early proerythroblasts died.
The researchers noted that it is not clear how excess heme induces cell death in RBC precursors, but they said it likely involves both ferroptosis and apoptosis.
Regardless of the mechanism of cell death, the team found that treating the patients’ cells with succinylacetone (10 mM), a compound that blocks heme synthesis, improved RBC production.
The treatment improved RBC production in DBA and del(5q) MDS marrow cultures by 68% to 95% (P=0.03 to 0.05). In comparison, RBC production in control marrow cultures decreased by 4% to 13%.
The researchers said their experiments revealed additional important findings. First, they found that erythroid differentiation in the marrow cultures “excellently” phenocopied erythroid differentiation in vivo. This suggests these cultures can serve as a reliable platform in preclinical studies.
Second, the team said the fact that epigenetic differences between RBC precursors can lead to their preferential death or survival has broad implications. And querying the cells that preferentially survive could provide important insights.
