NEOPLASTIC HEMATOPOIETIC CELL GROWTH--INTERACTIONS WITH RETROVIRUSES

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Binding of the regulatory peptide, interleukin 2 (IL 2) to its specific receptor is a prerequisite for activated T-lymphocytes to grow. Recombinant purified IL 2 has been used to identify post-receptor events important in mediating IL 2 function. (Ca++) mobilization, protein kinase C activation and phosphoinositol hydrolysis has all been found to correlate with IL 2 induced gene activation. The genes activated by IL 2 have included those for the IL 2 receptor, gamma interferon and the proto-oncogenes, c-fos, c-myb and c-myc. IL 2 stimulation of IL 2 receptor gene transcription results in an increase of receptors on the cell surface of low affinity for IL 2. Further studies of IL 2 receptor distribution has shown it also to be expressed on immature thymocytes, monocytes/macrophages, mast cells and a variety of hematopoietic progenitor cells. In these cells, the IL 2 receptor gene is under the transscriptional control of hematopoietic growth factors such as interleukin-3 and granulocyte/macrophage colony stimulating factor. Studies were conducted concerning the mechanism of myeloid cell differentiation. Variants of the murine myelomonocytic leukemia cell line such as WEHI-3B D+ which can be induced to differentiate into monocyte/macrophages and the WEHI-3B D- is unresponsive to these inducers were developed. The unresponsive cell line was induced to differentiate to granulocytes as well as monocytes by 1,25 dihydroxy-cholcalciferol (1,25 (OH)2 D3), the biologically active metabolite of Vitamin D3. The differentiation of both cell types was accompanied by cessation of cellular growth accompanies changes in morphologic and cytochemical properties of the cells. This suggests that leukemic cells unresponsive to differentiation agents acting at the cell surface retain their ability to differentiate in response to agents that do not act via the plasma membrane such as 1,25 (OH)2 D3 which has cytosolic/nuclear receptors. Regulation of proto-oncogene transcription was also studied in these cell lines. Expression of c-fos, c-myc and c-myb was identical in the subclones whether the cells differentiated or not suggesting that expression of these genes was not sufficient to induce differentiation.