Disruption of the estrogen receptor β gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis

Gil Jin Shim, Ling Wang, Sandra Andersson, Noémi Nagy, Loránd Levente Kis, Qinghong Zhang, Sari Mäkelä, Margaret Warner, Jan Åke Gustafsson

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132 Scopus citations

Abstract

Proliferation of pluripotent, bone marrow stem cells, which develop to lymphoid and myeloid progenitors, is negatively regulated by estrogen. Although in estrogen deficiency and in estrogen receptor knockout mice there is significant alteration in bone marrow hematopoiesis, the effects of aging on estrogen receptor deficiencies in mice have not been investigated yet. In this study we show that by 1.5 years of age, estrogen receptor β knockout (ERβ-/-) mice develop pronounced splenomegaly that is much more severe in females than in males. Further characterization of these mice revealed myelogenous hyperplasia in bone marrow, an increase in the number of granulocytes and B lymphocytes in blood, lymphadenopathy, and infiltration of leukocytes in the liver and lung. Analysis by flow cytometry of the bone marrow cells revealed that the percentage and total number of Gr-1hi/Mac-1hi-positive granulocytes were increased by 15-30% and 100%, respectively. The numbers of B cells in the bone marrow and spleen were significantly higher in ERβ-/- mice than in WT littermates. Some of the ERβ-/- mice also had a severe lymphoproliferative phenotype. Thus the absence of ERβ results in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. Our results indicate a previously unknown role for ERβ in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggest that the ERβ-/- mouse is a potential model for myeloid and lymphoid leukemia. Furthermore, we suggest that ERβ agonists might have clinical value in the treatment of leukemia.

Original languageEnglish (US)
Pages (from-to)6694-6699
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number11
DOIs
StatePublished - May 27 2003

ASJC Scopus subject areas

  • General

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