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Red blood cells

In studying Diamond-Blackfan anemia (DBA), researchers have found evidence to suggest that ribosome levels play a key role in hematopoiesis.

The researchers found that a reduction in ribosomes is responsible for the disruption in red blood cell production observed in patients with DBA.

This reduction in ribosomes impairs the translation of certain messenger RNAs (mRNAs), which inhibits erythroid lineage commitment in hematopoietic stem and progenitor cells (HSCPs).

The researchers said this work has provided insight into how lineage commitment functions normally and in the setting of DBA.

Vijay Sankaran, MD, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues described these findings in Cell.

The team noted that most cases of DBA are caused by heterozygous loss-of-function mutations in ribosomal protein (RP) genes, which result in RP haploinsufficiency.

Past research revealed DBA-causing mutations in the transcription factor GATA1. Subsequent work showed that RP haploinsufficiency results in reduced translation of GATA1 mRNA, and increasing GATA1 protein levels can reduce the erythroid defects in DBA cells.

However, the mechanisms underlying these phenomena were unclear.

In the current study, the researchers found that DBA-associated perturbations reduced ribosome levels but did not affect the composition of ribosomes.

“There has been controversy over whether a ribosomal protein mutation changes the composition of the ribosomes or the quantity of the ribosomes,” Dr Sankaran said. “We know now that it is the latter.”

The researchers said the reduction of ribosome levels was largely promoted through reduced translation of RP mRNAs.

The team identified 525 transcripts with translation efficiencies that were downregulated by RP haploinsufficiency. They said a subset of these transcripts, including GATA1, have proven essential for hematopoietic cell growth and are upregulated during early erythropoiesis.

The researchers confirmed their prior findings that translation of GATA1 mRNA is decreased by about 2-fold in differentiating HSPCs with RP haploinsufficiency.

The team also found that GATA1 has “unique” 5’ untranslated region features that confer sensitivity to ribosome levels.

Taken together, these findings suggest the presence of GATA1 proteins in HSPCs helps prime them for erythroid lineage commitment. Without enough ribosomes to produce enough GATA1 proteins, the HSPCs never receive the signal to become red blood cells.

“This raises the question of whether we can design a gene therapy to overcome the GATA1 deficiency,” Dr Sankaran said. “We now have a tremendous interest in this approach and believe it can be done.”

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