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Activating Mutations in the N- and K-ras Oncogenes Differentially Affect the Growth Properties of the IL-6-dependent Myeloma Cell Line ANBL6¹

Departments of Laboratory Medicine and Pathology [D. B., P. L., N. S., T. W. L.] and Biochemistry and Institute of Human Genetics [B. V. N.], the Cancer Center [N. S., T. W. L., B. V. N.], and the Center for Immunology [T. W. L., B. V. N.], University of Minnesota, Minneapolis, Minnesota 55455; and Mayo Clinic, Rochester, Minnesota 55905 [D. J.]

Although the underlying genetic defect in multiple myeloma is unknown, activating mutations in the N- and K-ras oncogenes are common. Recent studies have suggested that ras mutations are associated with disease progression. We have introduced an activated N-ras12, N-ras61, or K-ras12 cDNA into the interleukin 6 (IL-6)-dependent multiple myeloma cell line ANBL6 to determine the effect of N- and K-ras on the growth/death properties of ANBL6. All three transduced cell populations demonstrate a growth advantage over the parent ANBL6 when propagated on normal human bone marrow stromal cells. In the absence of bone marrow stromal cells, augmentation of growth was observed in all three mutant ras-expressing populations at optimal and suboptimal concentrations of IL-6. Furthermore, in the absence of IL-6, all mutant ras populations demonstrated an augmentation in DNA synthesis when compared to the parent ANBL6. However, growth of the K-ras12 population in the absence of IL-6 was significantly inhibited when compared to the mutant N-ras populations. This could be explained by the observation that in the absence of IL-6, N-ras12 and N-ras61 suppress apoptosis, whereas K-ras12 does not. We also found that mutant ras expression could result in early protection from glucocorticoid-induced apoptosis similar to that observed by the addition of IL-6. However, the combination of mutant ras and IL-6 could completely block the glucocorticoid induction of apoptosis in long-term cultures. These data suggest that mutations in different ras family members may have similar or distinct effects on myeloma tumor growth and death and may alter the response to glucocorticoid treatment.

¹ Supported by NIH Grant PO1 CA62242, a grant from the Leukemia Task Force (to B. V. N.), and NIH Grant R01 CA31685 (to T. W. L.); D. B. was supported by Immunology Training Grant T32 A1-07313.

² To whom requests for reprints should be addressed, at Institute of Human Genetics, Box 206 UMHC. University of Minnesota, Minnesota, Minneapolis, MN 55455. Phone: (612) 624-9944; Fax: (612) 626-7031.

Received 12/23/96. Accepted 4/ 3/97.

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