L-Leucine improves the anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q) MDS by activating the mTOR pathway.
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.
Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. beth.payne@cancer.ucl.ac.uk
Elspeth M
EM
Payne
Maria
M
Virgilio
Anupama
A
Narla
Hong
H
Sun
Michelle
M
Levine
Barry H
BH
Paw
Nancy
N
Berliner
A Thomas
AT
Look
Benjamin L
BL
Ebert
Arati
A
Khanna-Gupta
D029503:Anemia, Diamond-Blackfan / Q000097:blood / Q000188:drug therapy* / Q000196:embryology / Q000378:metabolism; D000748:Anemia, Macrocytic / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D006397:Hematinics / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007930:Leucine / Q000494:pharmacology / Q000627:therapeutic use*; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors
D006397:Hematinics; D034741:RNA, Small Interfering; D012269:Ribosomal Proteins; D029961:Zebrafish Proteins; C039747:ribosomal protein S14; C040343:ribosomal protein S19; D058570:TOR Serine-Threonine Kinases; D007930:Leucine