Novel selective regulation of hematopoietic progenitor self-renewal, survival and proliferation by estrogens has therapeutic potential in myeloproliferative neoplasms

Estrogens are potential regulators of the hematopoietic stem cell (HSC) niche and have effects on mature hematopoietic cells; however, whether estrogen signaling directly regulates normal and malignant HSC remains unclear. We demonstrate differential expression and specific roles of estrogen receptors (ER) in hematopoietic progenitors. ERa activation in short-term HSC and multipotent progenitors induced apoptosis. In contrast, the selective ER modulator (SERM) tamoxifen induced proliferation of quiescent long-term HSC, altered their self-renewal signature and compromised hematopoietic reconstitution following myelotoxic stress. Treatment with tamoxifen alone abolished hematopoietic progenitor expansion induced by JAK2V617F by restoring normal levels of apoptosis, blocked JAK2V617F-induced myeloproliferative neoplasm in vivo, and sensitized MLL-AF9+ leukemias to chemotherapy. Tamoxifen showed selective effects on mutant cells compared to normal ones, and had only a minor impact on steady-state hematopoiesis in disease-free animals. These results uncover specific regulation of hematopoietic progenitors by estrogens and potential anti-leukemic properties of SERM Overall design: LT-HSCs, ST-HSCs and MPPs sorted from the bone marrow of mice treated with tamoxifen or vehicle (3 biological replicates per group)

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Sánchez-Aguilera A, Arranz L, Martín-Pérez D, García-García A, Stavropoulou V, Kubovcakova L, Isern J, Martín-Salamanca S, Langa X, Skoda RC, Schwaller J, Méndez-Ferrer S