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ORIGINAL RESEARCH ARTICLE

Signaling Pathways Implicated in Hematopoietic Progenitor Cell Proliferation and Differentiation

Diana Bugarski¹, Aleksandra Krsti, Slavko Mojsilovi, Marija Vlaki, Marijana Petakov, Gordana Jovi, Nevenka Stojanovi and Pavle Milenkovi

Institute for Medical Research, Beograd, Serbia and Montenegro

To whom requests for reprints should be addressed at ¹ The Institute for Medical Research, Dr Subotia 4, P.O. Box 102, 11129 Beograd, Serbia and Montenegro. E-mail: dianab{at}imi.bg.ac.yu

The objective of this study was to investigate the signal transduction pathways associated with the clonal development of myeloid and erythroid progenitor cells. The contribution of particular signaling molecules of protein tyrosine kinases (PTKs), mitogen-activated protein (MAP) kinase, and PI-3 kinase signaling to the growth of murine bone marrow colony forming unit–granulocyte-macrophage (CFU-GM) and erythroid (burst forming unit-erythroid [BFU-E] and colony forming unit-erythroid [CFU-E]) progenitors was examined in studies performed in the presence or absence of specific signal transduction inhibitors. The results clearly pointed to different signal transducing intermediates that are involved in cell proliferation and differentiation depending on the cell lineage, as well as on the progenitors’ maturity. Lineage-specific differences were obtained when chemical inhibitors specific for receptor- or nonreceptor-PTKs, as well as for the main groups of distinctly regulated MAPK cascades, were used because all of these compounds suppressed the growth of erythroid progenitors, with no major effects on myeloid progenitors. At the same time, differential involvement of MEK/extracellular signal-regulated kinase (ERK) MAPK transduction pathway was observed in the proliferation and/or differentiation of early, BFU-E, and late, CFU-E, erythroid progenitor cells. The results also demonstrated that phosphatydylinositol (PI)-3 kinase and nuclear factor kappaB (NF-B) transcriptional factor were required for maintenance of both myeloid and erythroid progenitor cell function. Overall, the data obtained indicated that committed hematopoietic progenitors express a certain level of constitutive signaling activity that participates in the regulation of normal steady-state hematopoiesis and point to the importance of evaluating the impact of signal transduction inhibitors on normal bone marrow when used as potential therapeutic agents.

Key Words: signal transduction • hematopoiesis • bone marrow cells • hematopoietic progenitors