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Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors

Nature volume 453, pages 228–232 (2008)Cite this article

Abstract

Haematopoiesis is maintained by a hierarchical system where haematopoietic stem cells (HSCs) give rise to multipotent progenitors, which in turn differentiate into all types of mature blood cells1. HSCs maintain themselves for the lifetime of the organism because of their ability to self-renew. However, multipotent progenitors lack the ability to self-renew, therefore their mitotic capacity and expansion potential are limited and they are destined to eventually stop proliferating after a finite number of cell divisions1,2. The molecular mechanisms that limit the proliferation capacity of multipotent progenitors and other more mature progenitors are not fully understood2,3. Here we show that bone marrow cells from mice deficient in three genes genetically downstream of Bmi1—p16Ink4a , p19Arf and Trp53 (triple mutant mice; p16Ink4a and p19Arf are alternative reading frames of the same gene (also called Cdkn2a) that encode different proteins)—have an approximately 10-fold increase in cells able to reconstitute the blood long term. This increase is associated with the acquisition of long-term reconstitution capacity by cells of the phenotype c-kit+Sca-1+Flt3+CD150-CD48-Lin-, which defines multipotent progenitors in wild-type mice4,5,6. The pattern of triple mutant multipotent progenitor response to growth factors resembles that of wild-type multipotent progenitors but not wild-type HSCs. These results demonstrate that p16Ink4a/p19Arf and Trp53 have a central role in limiting the expansion potential of multipotent progenitors. These pathways are commonly repressed in cancer, suggesting a mechanism by which early progenitor cells could gain the ability to self-renew and become malignant with further oncogenic mutations.

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Figure 1: Immunophenotypic frequency of HSCs and multipotent progenitors in wild-type and p16 Ink4a-/- p19 Arf-/- Trp53 -/- mice.
Figure 2: Long-term multi-lineage reconstitution by HSCs and multipotent progenitors from p16 Ink4a -/- p19 Arf -/- Trp53 -/- mice.
Figure 3: In vitro proliferation and colony formation of wild-type and triple mutant HSCs and multipotent progenitors.

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Acknowledgements

This work was supported by grants from the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases (to M.F.C).

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Authors and Affiliations

  1. Cellular and Molecular Biology Graduate Program, University of Michigan, 2966 Taubman Medical Library, Ann Arbor, Michigan 48109-0619, USA ,

    Omobolaji O. Akala

  2. Stanford Institute for Stem Cell Biology and Regenerative Medicine and Division of Hematology/Oncology, Internal Medicine, Stanford University, 1050 Arastradero Road, Palo Alto, California 93404, USA,

    Omobolaji O. Akala, Dalong Qian & Michael F. Clarke

  3. Department of Hematology/Oncology, Internal Medicine, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA,

    In-Kyung Park & Michael Pihalja

  4. Division of Hematology/Oncology, University of Rochester, Rochester, New York 14642, USA,

    Michael W. Becker

Authors
  1. Omobolaji O. Akala
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  2. In-Kyung Park
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  3. Dalong Qian
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  4. Michael Pihalja
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  5. Michael W. Becker
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  6. Michael F. Clarke
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Corresponding author

Correspondence to Michael F. Clarke.

Supplementary information

The file contains Supplementary Figures 1-9 with Legends and Supplementary Tables 1-3

The Supplementary Figures and the Supplementary Tables summarize the main findings of the manuscript, and provide more data about rescue of HSC activity in Bmi1 deficient mice by deletion of Tp53 and acquisition of long-term reconstitution ability by p16Ink4a-/-p19Arf-/-Tp53-/- MPPs. (PDF 689 kb)

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Akala, O., Park, IK., Qian, D. et al. Long-term haematopoietic reconstitution by Trp53-/-p16Ink4a-/-p19Arf-/- multipotent progenitors. Nature 453, 228–232 (2008). https://doi.org/10.1038/nature06869

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