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NPM-MLF1 synergizes with Npm haploinsufficiency to enhance myeloid progenitor activity

Leukemia volume 26, pages 1110–1112 (2012)Cite this article

Myelodysplastic syndromes (MDS) are defined as clonal disorders of haematopoietic stem/progenitor cells (HSPCs), characterized by ineffective haematopoiesis, peripheral blood cytopenia, morphologic dysplasia and susceptibility to acute myeloid leukemia (AML).1, 2 Although cytogenetic abnormalities can be identified in about half the cases of MDS,3 relatively little is known about the genetic basis of MDS. The t(3;5)(q25;q34) translocation, creating the NPM-MLF1 fusion, has been found as a sole cytogenetic abnormality in MDS/AML patients.4 The nucleophosmin1 (NPM1) gene, located on 5q35, encodes a protein that takes part in a diversity of biological processes such as centrosome duplication, genomic stability and ribosome biogenesis.5 In MDS/AML patients with t(3;5), inactivation of one functional NPM allele resulting from the t(3;5)(q25;q34) translocation may be a key event in disease development. This concept is supported by the observations that Npm+/− mice exhibit some of the disease phenotypes resembling human MDS,6 and show predisposition to leukaemia.7 Therefore, we postulate that in patients, reduction in the expression levels of wild-type NPM1 is essential for the induction of MDS by NPM-MLF1.

In this report, we show that wild-type NPM and NPM-MLF1 physically interact. Reducing wild-type NPM levels enabled NPM-MLF1 to enhance the colony-forming activity of myeloid HPCs during a prolonged period of liquid culture. This was accompanied by concomitant increased expression of Hoxa9/10 and Meis1 genes, an important measure of the oncogenic potential of myeloid progenitors.8, 9, 10 Our data demonstrate that Npm haploinsufficiency is critical for NPM-MLF1 to enhance myeloid progenitor activity, essential for the initiation of MDS.

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Acknowledgements

We thank Dr Noriko Yoneda-Kato, Nara Institute of Science and Technology, for providing us with the NPM-MLF1 cDNA. We also thank Ayad Eddaoudi, UCL ICH Flow Cytometry Facility, for providing assistance with flow cytometry. This work was supported by the Elimination of Leukaemia Fund and the Great Ormond Street Hospital Special Purpose Fund.

Author contributions

W-H L and S S-A performed experiments and analyzed data. W-H L wrote the paper. PPP provided Npm+/− mice. HJB, OW and JB designed the project. OW and JB revised the manuscript critically.

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Authors and Affiliations

  1. Molecular Haematology and Cancer Biology Unit, UCL Institute of Child Health, London, UK

    W-H Lee, S Salek-Ardakani, J de Boer & O Williams

  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    P P Pandolfi

  3. Division of Cell and Molecular Biology, Immunology and Infection Section, Imperial College, London, UK

    H J M Brady

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  1. W-H Lee
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  2. S Salek-Ardakani
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Correspondence to O Williams.

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Lee, WH., Salek-Ardakani, S., Pandolfi, P. et al. NPM-MLF1 synergizes with Npm haploinsufficiency to enhance myeloid progenitor activity. Leukemia 26, 1110–1112 (2012). https://doi.org/10.1038/leu.2011.365

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