Distinct Inhibitory Effect of TGFβ on the Growth of Human Myeloid Leukemia Cells

Abstract

Hematopoiesis is the formation and development of blood cells. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation. Disruption of the steady state may cause the development of hematological diseases, such as acute (AML) or chronic myelogenous leukemia (CML). All mature blood cells ultimately originate from a rare population of primitive pluripotent (multipotential) stem cells. The pluripotent stem cells possess selfrenewal and multi-lineage differentiation potential. The latter process leads to two major multipotent progenitors: myeloid progenitors and lymphoid progenitors. The myeloid progenitors have the ability to differentiate into mature white cells, erythrocytes, megakaryocytes/platelets and mast cells; whereas the lymphoid progenitors cells mainly produce mature T, NK, and B lymphocytes. Production of myeloid lineage cells is a highly complex process involving the balance between cell proliferation and differentiation, which is regulated by growth stimulating or inhibiting signals. Transforming Growth Factor-beta (TGF┚) is a pleiotropic growth factor and is one of the major regulators of hematopoiesis (Fortunel NO et al. 2000). A major effect of TGF┚ on hematopoietic cells is inhibitory (Hu X et al 1999, Batard P et al. 2000, Ducos K et al. 2000, Fortunel NO 2000) although its stimulatory effect has also been observed in some types of blood cells (Keller JR 1990, 1992). Due to its importance in the understanding human diseases including leukemia, over past 20 years, the mechanisms responsible for TGF┚-induced growth inhibition or stimulation have been a major area of investigation and considerable insights into its action mechanisms have been learned. This review highlights recent progress in understanding regulatory role of TGF┚ and its signaling pathways in various types of cells with a focus on human myeloid leukemia cells.