Estrogen Signaling Selectively Induces Apoptosis of Hematopoietic Progenitors and Myeloid Neoplasms without Harming Steady-State Hematopoiesis

• Published in: Cell stem cell Vol. 15; no. 6; pp. 791 - 804
• Main Authors: Sánchez-Aguilera, Abel, Arranz, Lorena, Martín-Pérez, Daniel, García-García, Andrés, Stavropoulou, Vaia, Kubovcakova, Lucia, Isern, Joan, Martín-Salamanca, Sandra, Langa, Xavier, Skoda, Radek C., Schwaller, Jürg, Méndez-Ferrer, Simón
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.12.2014
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cells, Cultured; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Hematopoiesis - drug effects; Hematopoiesis - genetics; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Leukemia - drug therapy; Leukemia - metabolism; Leukemia - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation - genetics; Myeloid Progenitor Cells - drug effects; Myeloid Progenitor Cells - physiology; Oncogene Proteins, Fusion - metabolism; Selective Estrogen Receptor Modulators - administration & dosage; Signal Transduction; Tamoxifen - administration & dosage; Xenograft Model Antitumor Assays
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2014.11.002

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 JAK2V617F-induced myeloproliferative neoplasm in vivo, induced apoptosis of human JAK2V617F+ 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. [Display omitted] •Hematopoietic stem and multipotent progenitor cells (MPPs) express ERα•ERα activation induces apoptosis of MPPs and proliferation of LT-HSCs•Tamoxifen blocks JAK2V617F-induced myeloproliferative neoplasia in mice•Tamoxifen enhances chemotherapy response of MLL-AF9-induced leukemias In mice, activation of estrogen receptor (ER) signaling induces apoptosis in multipotent hematopoietic progenitors but induces proliferation and compromises function of HSCs in a reversible manner. Tamoxifen induces apoptosis of MLL-AF9+ blasts, improving conventional chemotherapy, and tamoxifen alone blocks JAK2V617F-induced myeloproliferative neoplasm by restoring normal apoptosis levels in mutant cells.