The regulatory mechanism of IL-6-dependent proliferation of human myeloma cells.

Multiple myeloma (MM) is a malignant tumor of plasma cells in the bone marrow. Interleukin 6 (IL-6) is an indispensable growth factor for myeloma cells. The heterogeneity of myeloma cells are the characteristics of MM, categorized into five sub-populations, two immature cells, MPC-1<PRE>-</PRE> CD49e<PRE>-</PRE> CD45<PRE>+/-</PRE>, intermediate cells, MPC-1<PRE>+</PRE> CD49e<PRE>-</PRE> CD45<PRE>+/-</PRE>, and mature cells, MPC-1<PRE>+</PRE> CD49e<PRE>+</PRE> CD45<PRE>+</PRE>. Only MPC-1<PRE>-</PRE> CD49e<PRE>-</PRE> CD45<PRE>+</PRE> immature cells (∼2% of total myeloma cells) respond to IL-6 to proliferate. CD45 protein tyrosine phosphatase is the determinant of IL-6 dependent cell growth of myeloma cells, although well studied IL-6 signal transducing factors, such as, IL-6Ra, gp130, Jak2, STAT3, and MAPK, are activated and involved in the process. Immature CD45<PRE>-</PRE> cells converted to CD45<PRE>+</PRE> cells after IL-6 stimulation both in U266 cells and sorted myeloma cells from the bone marrow aspirates of MM patients. CD45<PRE>-</PRE> cells are relatively resistant to serum starvation compared to CD45<PRE>+</PRE> cells. Because IL-6 level in the bone marrow is low even in MM patients, the CD45<PRE>-</PRE> phenotype of myeloma cells may protect the cells from apoptosis. These findings of a tuning effect of CD45 on myeloma cell proliferation may aid the study of IL-6 dependent proliferation of myeloma cells and lead to the development of new therapies for MM patients.