REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

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The overall goal of this section is to better understand the interactions between positive and negative regulators of hematopoietic stem cells. Synergistic effects of hematopoietic growth factors (HGFs) on BM growth and colony formation were consistently preceded by increased CSF receptor expression on enriched BM progenitor cells, but not on unfractionated cells. Upregulation of CSF receptor expression was observed after 6 hrs, maximal by 24 hrs and preceded detectable differentiation and did not require cell division since nocodazole, an inhibitor of mitosis, blocked CSF mediated cellular growth but not receptor upregulation. Single cell assays showed that growth factor synergy was a direct effect and correlated with the ability to upregulate CSF receptor expression. Furthermore, we have shown that TGF beta1 has bidirectional effects on hematopoietic progenitor cells; however, the mechanism(s) of action mediating these responses remain unknown. We have found that the effects of TGF beta1 on CSF-induced growth of BM progenitor cells is directly correlated with modulation of CSF receptor expression. Specifically, TGF beta1 mediated inhibition of IL 3-stimulated BM proliferation was preceded by reduced IL 3 receptor expression, while upregulation of GM-CSF receptors preceded the synergistic effect of TGF beta1 on GM-CSF-stimulated proliferation. Similarly, TNF alpha has been reported to either inhibit or stimulate CSF-induced hematopoietic progenitor cell growth. We found that the direct effects of TNF alpha on the murine BMC and enriched multipotential progenitors are only inhibitory, and correlated with its ability to transdown-modulate the receptor expression for the CSFs. Also, MIP 1alpha was shown to directly enhance IL 3- and GM-CSF-induced growth of Lin- cells in single cell assays. However, MIP 1alpha like TGF beta1 inhibited both the IL 3 and GM-CSF-induced growth of more primitive Lin-, Thy-1+ cells. Thus, modulation of growth factor receptor expression and direct bidirectional effects are common features in cytokine regulation of primitive hematopoietic cell growth.