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A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome

Nature Medicine volume 16, pages 59–66 (2010)Cite this article

Abstract

The identification of the genes associated with chromosomal translocation breakpoints has fundamentally changed understanding of the molecular basis of hematological malignancies. By contrast, the study of chromosomal deletions has been hampered by the large number of genes deleted and the complexity of their analysis. We report the generation of a mouse model for human 5q– syndrome using large-scale chromosomal engineering. Haploinsufficiency of the Cd74–Nid67 interval (containing Rps14, encoding the ribosomal protein S14) caused macrocytic anemia, prominent erythroid dysplasia and monolobulated megakaryocytes in the bone marrow. These effects were associated with defective bone marrow progenitor development, the appearance of bone marrow cells expressing high amounts of the tumor suppressor p53 and increased bone marrow cell apoptosis. Notably, intercrossing with p53-deficient mice completely rescued the progenitor cell defect, restoring common myeloid progenitor and megakaryocytic-erythroid progenitor, granulocyte-monocyte progenitor and hematopoietic stem cell bone marrow populations. This mouse model suggests that a p53-dependent mechanism underlies the pathophysiology of the 5q– syndrome.

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Figure 1: Schematic of the CDR in human 5q– syndrome and its alignment with mouse regions of synteny.
Figure 2: Deletion of the Cd74–Nid67 interval leads to macrocytic anemia.
Figure 3: Blood and bone marrow cell proportions in Cd74–Nid67-deleted mice.
Figure 4: Dysplastic bone marrow from Cd74–Nid67-deleted mice.
Figure 5: Characterization of hematopoietic progenitor cells, p53 expression and apoptotic cells in the bone marrow of Cd74–Nid67-deleted mice.
Figure 6: Deletion of Trp53 reverses the progenitor cell deficits resulting from deletion of the Cd74–Nid67 interval.

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Acknowledgements

Thanks go to members of the McKenzie lab for their comments on the manuscript. We are grateful to the Laboratory of Molecular Biology animal facility staff, especially V. Smith. We are also grateful to K. Grobe (University of Munster) for providing blood from the Ndst1+/− mice and T. Rabbitts (Leeds Institute of Molecular Medicine) for providing Lmo2Cre mice. A.N.J.M., D.R.H., S.L.-A., A.L.L., J.S.W., J.B. and A.J.W. were funded by Leukaemia Research UK.

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Author notes

  1. Jillian L Barlow, Lesley F Drynan, Duncan R Hewett and Luke R Holmes: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    Jillian L Barlow, Lesley F Drynan, Duncan R Hewett, Luke R Holmes, Silvia Lorenzo-Abalde, Alison L Lane, Helen E Jolin, Richard Pannell, Angela J Middleton, See Heng Wong, Alan J Warren & Andrew N J McKenzie

  2. Nuffield Department of Clinical Laboratory Sciences, Leukaemia Research Fund Molecular Haematology Unit, John Radcliffe Hospital, Oxford, UK

    James S Wainscoat & Jacqueline Boultwood

  3. Department of Haematology, University of Cambridge, Cambridge, UK

    Alan J Warren

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  1. Jillian L Barlow
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Contributions

A.N.J.M. conceived of and designed the project; A.N.J.M., D.R.H., L.R.H., A.L.L., L.F.D., R.P. and H.E.J. designed and generated gene-targeted mice; A.N.J.M., J.L.B., L.F.D., S.L.-A., A.L.L., A.J.M., J.B., S.H.W., J.S.W. and A.J.W. analyzed hematopoiesis; J.S.W. and J.B. performed gene expression profiling analysis and provided unpublished information; H.E.J. performed annexin V analysis. All authors contributed to the writing of the paper.

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Correspondence to Andrew N J McKenzie.

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Barlow, J., Drynan, L., Hewett, D. et al. A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q– syndrome. Nat Med 16, 59–66 (2010). https://doi.org/10.1038/nm.2063

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