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.

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

“…Notably, we also found a statistically significant benefit in survival in female mice treated with LHRH-Ant after L-TBI (Fig. S1d), although more modest in comparison to the benefit observed in male mice; this difference is potentially due to the differential effects of estrogen and testosterone on HSC function 4,5 .…”

The bulk of the hematopoietic stem cell population is dispensable for murine steady-state and stress hematopoiesis

“…Also, this setup did not result in HSC recovery. The limited LT-HSC recovery in HSPC-depleted mice was not caused by persistent bioactivity of TAM 30 as determined by transplantation of uninduced HSC-CreERT…”

27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy

“…Pregnant Cyp27a1 -/-mice did not significantly differ from pregnant WT mice in terms of bone marrow cellularity or the numbers of HSCs or other progenitors in the bone marrow ( Figure 5A). In contrast, pregnant WT mice exhibited substantial increases in the numbers of HSCs, MPPs, HPC-1 cells, HPC-2 cells, CMPs, GMPs, MEPs, and erythroid lineage cells in the spleen as comtors (19). E2 treatment also induced apoptosis in HPCs, as indicated by increased annexin V binding to exteriorized phosphatidylserine ( Figure 1D).…”