ROLE OF CDK4 AND P16(INK4A) IN INTERLEUKIN-6-MEDIATED GROWTH OF MULTIPLE-MYELOMA

Interleukin-6 (IL-6) promotes growth of human multiple myeloma (MM) ce lls via phosphorylation of retinoblastoma protein (pRB) We therefore e xamined the kinetics of cyclin-dependent kinase 4 (CDK4), p16(INK4A), and pRB activation during IL-6-mediated patient MM cell growth compare d with growth of IL-6 unresponsive patient plasma cell leukemia (PCL) cells. CDK4 protein was more strongly expressed in PCL cells than in M M cells. On the other hand, p16 protein was present in MM cells but un detectable in PCL cells. Interestingly, IL-6 induced peak proliferatio n of MM cells at days 1-3, with a return to baseline levels of DNA syn thesis by days 6-9 in spite of replenishing IL-6. In these cells, IL-6 triggered a sustained increase in CDK4 by day 1 and a gradual increas e in p16 to day 9, The progressive increase in p16 without further inc rements in CDK4 resulted in a shift from cyclin DP-CDK4/CDK6 binding a t days 1-3 to p16-CDK4/CDK6 complex formation at days 6-9. Both phosph orylated pRB and dephosphorylated pRB were present initially in patien t MM cells; IL-6 triggered a shift to phosphorylated pRB and G1 to S t ransition at days 1-3, with return to baseline levels of dephosphoryla ted pRB and related G1 growth arrest by day 9, No similar changes in C DK4, p16, or cell cycle profile were observed in IL-6 nonresponsive PC L cells. Our data therefore suggest a feedback mechanism in IL-6-media ted MM cell growth which is absent in IL-6 nonresponsive PCL cells.