title: Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.
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.
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain. Electronic address: abel.sanchez-aguilera@cnic.es.
authors.forename: Abel
authors.initials: A
authors.lastname: Sánchez-Aguilera
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Arranz
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martín-Pérez
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: García-García
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Vaia
authors.initials: V
authors.lastname: Stavropoulou
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kubovcakova
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Isern
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Martín-Salamanca
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Langa
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Radek C
authors.initials: RC
authors.lastname: Skoda
authors.affiliation: Department of Biomedicine, University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: Stem Cell Niche Pathophysiology Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain. Electronic address: smendez@cnic.es.
authors.forename: Simón
authors.initials: S
authors.lastname: Méndez-Ferrer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D023461:Myeloid Progenitor Cells / Q000187:drug effects* / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D015398:Signal Transduction; D013629:Tamoxifen / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; C551356:MLL-AF9 fusion protein, mouse; D015514:Oncogene Proteins, Fusion; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2