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Enhanced polyamine catabolism disturbs hematopoietic lineage commitment and leads to a myeloproliferative disease in mice overexpressing spermidine/spermine N 1-acetyltransferase

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Abstract

Spermidine/spermine N 1-acetyltransferase (SSAT) regulates intracellular polyamine levels by catabolizing spermidine and spermine which are essential for cell proliferation and differentiation. Hematological characterization of SSAT overexpressing mice (SSAT mice) revealed enhanced myelopoiesis and thrombocytopoiesis leading to increased amounts of myeloid cells in bone marrow, peripheral blood, and spleen compared to wild-type animals. The level of SSAT activity in the bone marrow cells was associated with the bone marrow cellularity and spleen weight which both were significantly increased in SSAT mice. The result of bone marrow transplantations indicated that both the intrinsic SSAT overexpression of bone marrow cells and bone marrow microenvironment had an impact on the observed hematopoietic phenotype. The Lineage-negative Sca-1+ c-Kit+ hematopoietic stem cell (HSC) compartment in SSAT mice, showed enhanced proliferation, increased proportion of long-term HSCs and affected expression of transcription factors associated with lineage priming and myeloid differentiation. The proportions of common myeloid and megakaryocytic/erythroid progenitors were decreased and the proportion of granulocyte–macrophage progenitors was increased in SSAT bone marrow. The data suggest that SSAT overexpression and the concomitantly accelerated polyamine metabolism in hematopoietic cells and bone marrow microenvironment affect lineage commitment and lead to the development of a mouse myeloproliferative disease in SSAT mice.

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Abbreviations

SSAT:

Spermidine/spermine N 1-acetyltransferase

ODC:

Ornithine decarboxylase

AdoMetDC:

s-adenosylmethionine decarboxylase

HSCs:

Hematopoietic stem cells

AML:

Acute myeloid leukemia

CML:

Chronic myeloid leukemia

CMP:

Common myeloid progenitors

MEP:

Megakaryocyte-erythroid progenitors

GMP:

Granulocyte/macrophage progenitors

LT-HSCs:

Long-term hematopoietic stem cells

LSK cells:

Lineage-negative Sca+ c-Kit+ cells

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Acknowledgments

We gratefully acknowledge Ms Tuula Reponen, Ms Anne Karppinen, Ms Arja Korhonen, and Ms Marita Heikkinen for their skilful technical assistance. We thank the radiation therapy unit of Kuopio University Hospital for irradiation of the mice.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland

    Sini Pirnes-Karhu, Petri I. Mäkinen, Sara Wojciechowski, Sisko Juutinen, Jari Koistinaho, Leena Alhonen & Anne Uimari

  2. Laboratory of Eastern Finland, Kuopio, Finland

    Pentti Mäntymaa

  3. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland

    Reijo Sironen

  4. Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland

    Reijo Sironen

  5. Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland

    Reijo Sironen

  6. Department of Medical Microbiology and Immunology, Institute of Diagnostics, University of Oulu, Oulu, Finland

    Sohvi Hörkkö

  7. Clinical Research Center of Oulu University Hospital, Oulu, Finland

    Sohvi Hörkkö

  8. Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

    Esa Jantunen

  9. Department of Medicine, Kuopio University Hospital, Kuopio, Finland

    Esa Jantunen

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  1. Sini Pirnes-Karhu
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  2. Pentti Mäntymaa
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  10. Leena Alhonen
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  11. Anne Uimari
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Correspondence to Anne Uimari.

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Pirnes-Karhu, S., Mäntymaa, P., Sironen, R. et al. Enhanced polyamine catabolism disturbs hematopoietic lineage commitment and leads to a myeloproliferative disease in mice overexpressing spermidine/spermine N 1-acetyltransferase. Amino Acids 46, 689–700 (2014). https://doi.org/10.1007/s00726-013-1546-5

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  • DOI: https://doi.org/10.1007/s00726-013-1546-5

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