Abstract
Haploinsufficiency of ribosomal proteins (RPs) 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, after 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 ongoing clinical trials of L-leucine as a therapeutic agent for DBA, and potentially for patients with del(5q) MDS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia, Diamond-Blackfan / blood
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Anemia, Diamond-Blackfan / drug therapy*
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Anemia, Diamond-Blackfan / embryology
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Anemia, Diamond-Blackfan / metabolism
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Anemia, Macrocytic / drug therapy
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Anemia, Macrocytic / metabolism
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Animals
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Animals, Genetically Modified
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Cells, Cultured
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Chromosome Deletion
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Chromosomes, Human, Pair 5 / metabolism
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Disease Models, Animal
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Embryo, Nonmammalian / drug effects
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Embryonic Development / drug effects*
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Hematinics / pharmacology
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Hematinics / therapeutic use
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Hematopoiesis / drug effects
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / immunology
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / pathology
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Humans
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Leucine / pharmacology
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Leucine / therapeutic use*
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Myelodysplastic Syndromes / drug therapy*
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Myelodysplastic Syndromes / embryology
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Myelodysplastic Syndromes / genetics
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Myelodysplastic Syndromes / metabolism
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RNA, Small Interfering
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Ribosomal Proteins / antagonists & inhibitors
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Signal Transduction / drug effects*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism*
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Up-Regulation / drug effects*
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Zebrafish
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Zebrafish Proteins / antagonists & inhibitors
Substances
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Hematinics
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RNA, Small Interfering
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Ribosomal Proteins
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Zebrafish Proteins
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ribosomal protein S14
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ribosomal protein S19
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TOR Serine-Threonine Kinases
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Leucine
Supplementary concepts
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Chromosome 5q Deletion Syndrome