L-Leucine improves anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q)MDS by activating the mTOR pathway

Haploinsufficiency of ribosomal proteins (RP) has been proposed to be the common basis for the anemia observed in Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome with loss of chromosome 5q (del(5q) MDS). We have modeled DBA and del(5q) MDS in zebrafish using antisense morpholinos to rps19 and rps14 respectively, and have demonstrated that, as in humans, haploinsufficient levels of these proteins lead to a profound anemia. To address the hypothesis that RP loss results in impaired mRNA translation, we treated Rps19 and Rps14 deficient embryos with the amino acid L-Leucine, a known activator of mRNA translation. This resulted in a striking improvement of the anemia associated with RP loss. We confirmed our findings in primary human CD34+ cells, following shRNA knockdown of RPS19 and RPS14. Furthermore, we showed that loss of Rps19 or Rps14 activates the mTOR pathway and this is accentuated by L-Leucine in both Rps19 and Rps14 morphants. This effect could be abrogated by rapamycin suggesting that mTOR signaling may be responsible for the improvement in anemia associated with L-Leucine. Our studies support the rationale for on-going clinical trials of L-Leucine as a therapeutic agent for DBA, and potentially for patients with del(5q)MDS.