title: Enhanced polyamine catabolism disturbs hematopoietic lineage commitment and leads to a myeloproliferative disease in mice overexpressing spermidine/spermine N¹-acetyltransferase.
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.
authors.affiliation: Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Pirnes-Karhu
authors.forename: Pentti
authors.initials: P
authors.lastname: Mäntymaa
authors.forename: Reijo
authors.initials: R
authors.lastname: Sironen
authors.forename: Petri I
authors.initials: PI
authors.lastname: Mäkinen
authors.forename: Sara
authors.initials: S
authors.lastname: Wojciechowski
authors.forename: Sisko
authors.initials: S
authors.lastname: Juutinen
authors.forename: Jari
authors.initials: J
authors.lastname: Koistinaho
authors.forename: Sohvi
authors.initials: S
authors.lastname: Hörkkö
authors.forename: Esa
authors.initials: E
authors.lastname: Jantunen
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Anne
authors.initials: A
authors.lastname: Uimari
mesh_terms: D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D005260:Female; D020869:Gene Expression Profiling; D006410:Hematopoiesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011073:Polyamines / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase