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Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis

Sánchez-Aguilera, Abel and Arranz, Lorena and Martín-Pérez, Daniel and García-García, Andrés and Stavropoulou, Vaia and Kubovcakova, Lucia and Isern, Joan and Martín-Salamanca, Sandra and Langa, Xavier and Skoda, Radek C. and Schwaller, Jürg and Méndez-Ferrer, Simón. (2014) Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis. Cell Stem Cell, 15 (6). pp. 791-804.

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Official URL: https://edoc.unibas.ch/62065/

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Abstract

Estrogens are potent regulators of mature hematopoietic cells; however, their effects on primitive and malignant hematopoietic cells remain unclear. Using genetic and pharmacological approaches, we observed differential expression and function of estrogen receptors (ERs) in hematopoietic stem cell (HSC) and progenitor subsets. ERα activation with the selective ER modulator (SERM) tamoxifen induced apoptosis in short-term HSCs and multipotent progenitors. In contrast, tamoxifen induced proliferation of quiescent long-term HSCs, altered the expression of self-renewal genes, and compromised hematopoietic reconstitution after myelotoxic stress, which was reversible. In mice, tamoxifen treatment blocked development of JAK2(V617F)-induced myeloproliferative neoplasm in vivo, induced apoptosis of human JAK2(V617F+) HSPCs in a xenograft model, and sensitized MLL-AF9(+) leukemias to chemotherapy. Apoptosis was selectively observed in mutant cells, and tamoxifen treatment only had a minor impact on steady-state hematopoiesis in disease-free animals. Together, these results uncover specific regulation of hematopoietic progenitors by estrogens and potential antileukemic properties of SERMs.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Kindliche Leukämie (Schwaller)
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Hämatologie > Molekulare Medizin (Skoda)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Hämatologie > Molekulare Medizin (Skoda)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Children's Hospital > Childhood Leukemia (Schwaller)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Experimental Hematology (Skoda)
UniBasel Contributors:Schwaller, Jürg and Skoda, Radek C.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Cell Press
ISSN:1934-5909
e-ISSN:1875-9777
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:01 Jun 2020 08:45
Deposited On:01 Jun 2020 08:45

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