Disruption of the estrogen receptor beta gene in mice causes myeloproliferative disease resembling chronic myeloid leukemia with lymphoid blast crisis.
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 beta knockout (ERbeta-/-) 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 ERbeta-/- mice than in WT littermates. Some of the ERbeta-/- mice also had a severe lymphoproliferative phenotype. Thus the absence of ERbeta results in a myeloproliferative disease resembling human chronic myeloid leukemia with lymphoid blast crisis. Our results indicate a previously unknown role for ERbeta in regulating the differentiation of pluripotent hematopoietic progenitor cells and suggest that the ERbeta-/- mouse is a potential model for myeloid and lymphoid leukemia. Furthermore, we suggest that ERbeta agonists might have clinical value in the treatment of leukemia.
Shim
Gil-Jin
GJ
Department of Medical Nutrition, Karolinska Institute, NOVUM, S-141 86 Huddinge, Sweden.
Wang
Ling
L
Andersson
Sandra
S
Nagy
Noémi
N
Kis
Loránd Levente
LL
Zhang
Qinghong
Q
Mäkelä
Sari
S
Warner
Margaret
M
Gustafsson
Jan-Ake
JA
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D047629:Estrogen Receptor beta; D005434:Flow Cytometry; D006098:Granulocytes / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism
D047629:Estrogen Receptor beta; D011960:Receptors, Estrogen