Novel Evidence That Pituitary Gonadotropins Directly Stimulate Human Leukemic cells—studies on Myeloid Cell Lines and Primary Patient AML and CML Cells

Background. It has been postulated that hematopoietic stem/progenitor cells (HSPCs) can become specified from a population of migrating primordial germ cells (PGCs) isolated from embryos. In support of this intriguing possibility, HSPCs and PGCs are both highly migratory populations of stem cells, and evidence has accumulated for the sharing of several mutated genes (e.g., Sall4) as well as chromosomal aberrations between germline tumors and leukemias or lymphomas, which suggests their common clonal origin. In fact, we recently observed that normal murine HSPCs express several functional receptors for pituitary gonadal hormones, such as follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), in addition to gonadal hormones including estrogens, androgen, and progesterone. Of note, the plasma levels of FSH and LH are elevated in older patients, which correlate with an increase in the incidence of myeloid leukemia.

Hypothesis. Based on this, we have hypothesized that gonadotropic hormones play a yet underappreciated role in human malignant hematopoiesis.

Materials and Methods. To address this issue, we performed a complex series of experiments employing human myeloid hematopoietic cell lines (KG-1a, K-562, U937, THP-1, HEL) and primary patient cells (AML, CML) to address the influence of pituitary sex hormones (FSH, LH, PRL) as well as gonadal sex hormones (androgen, estrogen, progesterone) on proliferation, migration, and adhesion of malignant cells. In addition, expression of the corresponding receptors was evaluated at the mRNA level by PCR, and their functionality was confirmed by signaling studies based on phosphorylation of major signal transduction pathways (AKT, MAPKp42/44, STAT). Results. We demonstrate for the first time that human myeloid leukemia cell lines express all pituitary gonadotropin and several gonadal hormone receptors and that FSH and LH receptors are functional on these cells, as evaluated by chemotaxis and adhesion assays. Moreover, FSH and LH receptors were expressed and functional on patient leukemic blasts in bone marrow (BM) and peripheral blood (PB). Human leukemic cells from cell lines and primary patient-derived cells also expressed some other gonadal hormone receptors (PRL-R, estrogen, progesterone, and androgen receptors), albeit at lower levels. Moreover, we observed that several human myeloid cell lines as well as primary patient leukemic cells responded to sex hormones by proliferation.

Conclusions. Our data are the first to indicate that pituitary-secreted gonadotropins stimulate migration, adhesion, and proliferation of leukemic cells. This latter effect seems to be direct, as the receptors for these hormones respond to stimulation by phosphorylation of intracellular pathways involved in cell proliferation. Established human myeloid leukemia cell lines and primary patient blasts also responded to stimulation by gonadal sex hormones. Finally, our studies provide further evidence supporting a developmental link between hematopoiesis and the germline.