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Activation of the mTOR signaling pathway by L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts

Leukemia volume 27, pages 1760–1763 (2013)Cite this article

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The ribosomopathies comprise a group of disorders characterized by aberrant ribosome biogenesis and function, resulting in specific disease phenotypes.1 The 5q- syndrome, the most distinct of all the myelodysplastic syndromes (MDS),2 is now recognized as a ribosomopathy. The CD34+ cells of patients with the 5q- syndrome show haploinsufficiency of the ribosomal protein gene RPS14,3, 4 which maps to the commonly deleted region (CDR) on chromosome 5q.2 It has been demonstrated that p53 activation secondary to RPS14 haploinsufficiency has an important role in the development of anemia in the 5q- syndrome.5, 6 Haploinsufficiency of RPS14 in the 5q- syndrome is associated with a block in the processing of pre-ribosomal RNA4 and deregulation of ribosomal- and translation-related genes.7 Defective ribosome biogenesis can result in a reduction in the efficiency of mRNA translation4, 8 and cultured erythroblasts from patients with the 5q- syndrome,8 and the ribosomopathy Schwachman-Diamond syndrome,9 exhibit impaired mRNA translation. Therefore, this defect in translation may represent a potential therapeutic target in the 5q- syndrome and other ribosomopathies.

Several lines of evidence indicate that the use of the amino acid L-leucine, a translation enhancer, may have some efficacy in the treatment of certain ribosomopathies. A patient with Diamond-Blackfan anemia (DBA) showed a marked improvement in anemia and became transfusion-independent following L-leucine therapy.10 Indeed, the addition of L-leucine to cultured lymphocytes obtained from patients with DBA was shown to result in an increase in translational efficiency.11 Recently, DBA and del(5q) MDS have been modeled in zebrafish using antisense morpholinos to knockdown rps19 and rps14, respectively.12 The treatment of the zebrafish models of DBA and del(5q) MDS with L-leucine resulted in an improvement in the hemoglobinization, red cell numbers and developmental defects.12 Similarly, the treatment of Rps19-deficient mice with L-leucine has been shown to result in an improvement in the anemia, with an increase in hemoglobin concentration and the number of erythrocytes.13 In a recent study, we have shown that L-leucine treatment of cultured human erythroblasts derived from CD34+ bone marrow cells with RPS14 knockdown and from MDS patients with del(5q) results in an increase in the cell proliferation, erythroid differentiation and mRNA translation.8 These studies suggest that L-leucine may have therapeutic effects in certain ribosomopathies by stimulating mRNA translation and cell growth.

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References

  1. Boultwood J, Yip BH, Vuppusetty C, Pellagatti A, Wainscoat JS . Activation of the mTOR pathway by the amino acid l-leucine in the 5q- syndrome and other ribosomopathies. Adv Biol Regul 2012; S2212-4926: 00086–3.

    Google Scholar 

  2. Boultwood J, Pellagatti A, McKenzie AN, Wainscoat JS . Advances in the 5q- syndrome. Blood 2010; 116: 5803–5811.

    Article  CAS  PubMed  Google Scholar 

  3. Boultwood J, Pellagatti A, Cattan H, Lawrie CH, Giagounidis A, Malcovati L et al. Gene expression profiling of CD34+ cells in patients with the 5q- syndrome. Br J Haematol 2007; 139: 578–589.

    Article  CAS  PubMed  Google Scholar 

  4. Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature 2008; 451: 335–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dutt S, Narla A, Lin K, Mullally A, Abayasekara N, Megerdichian C et al. Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells. Blood 2011; 117: 2567–2576.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barlow JL, Drynan LF, Hewett DR, Holmes LR, Lorenzo-Abalde S, Lane AL et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med 2010; 16: 59–66.

    Article  CAS  PubMed  Google Scholar 

  7. Pellagatti A, Hellstrom-Lindberg E, Giagounidis A, Perry J, Malcovati L, Della Porta MG et al. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol 2008; 142: 57–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yip BH, Pellagatti A, Vuppusetty C, Giagounidis A, Germing U, Lamikanra AA et al. Effects of L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts. Leukemia 2012; 26: 2154–2158.

    Article  CAS  PubMed  Google Scholar 

  9. Sen S, Wang H, Nghiem CL, Zhou K, Yau J, Tailor CS et al. The ribosome-related protein, SBDS, is critical for normal erythropoiesis. Blood 2011; 118: 6407–6417.

    Article  CAS  PubMed  Google Scholar 

  10. Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R . Successful treatment of a Diamond-Blackfan anemia patient with amino acid leucine. Haematologica 2007; 92: e66–e67.

    Article  CAS  PubMed  Google Scholar 

  11. Cmejlova J, Dolezalova L, Pospisilova D, Petrtylova K, Petrak J, Cmejla R . Translational efficiency in patients with Diamond-Blackfan anemia. Haematologica 2006; 91: 1456–1464.

    CAS  PubMed  Google Scholar 

  12. Payne E, Virgilio M, Narla A, Sun H, Levine M, Paw BH et al. L-Leucine improves anemia and developmental defects associated with Diamond-Blackfan anemia and del(5q)MDS by activating the mTOR pathway. Blood 2012; 120: 2214–2224.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jaako P, Debnath S, Olsson K, Bryder D, Flygare J, Karlsson S . Dietary L-leucine improves the anemia in a mouse model for Diamond-Blackfan anemia. Blood 2012; 120: 2225–2228.

    Article  CAS  PubMed  Google Scholar 

  14. Soulard A, Hall MN . SnapShot: mTOR signaling. Cell 2007; 129: 434.

    Article  PubMed  Google Scholar 

  15. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 2012; 149: 410–424.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Leukaemia and Lymphoma Research of the United Kingdom and in part by the National Institute for Health Research (NIHR) and by the Blood Theme in the NIHR Oxford Biomedical Research Centre, Oxford University Hospitals Trust. PV is a senior clinical investigator of FWO-Vlaanderen.

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Authors and Affiliations

  1. Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    B H Yip, C Vuppusetty, M Attwood, J S Wainscoat, A Pellagatti & J Boultwood

  2. Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany

    A Giagounidis

  3. Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-Universität, Düsseldorf, Germany

    U Germing

  4. Nuffield Division of Clinical Laboratory Sciences and National Blood Service Oxford Centre, Oxford, UK

    A A Lamikanra & D J Roberts

  5. Department of Translational Hematology and Oncology Research, Taussig Cancer Center, Cleveland, OH, USA

    J P Maciejewski

  6. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium

    P Vandenberghe

  7. Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy

    C Mecucci

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  1. B H Yip
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Correspondence to J Boultwood.

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Yip, B., Vuppusetty, C., Attwood, M. et al. Activation of the mTOR signaling pathway by L-leucine in 5q- syndrome and other RPS14-deficient erythroblasts. Leukemia 27, 1760–1763 (2013). https://doi.org/10.1038/leu.2013.20

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