Biochemical differences between SUDHL-1 and KARPAS 299 cells derived from t(2;5)-positive anaplastic large cell lymphoma are responsible for the different sensitivity to the anti proliferative effect of p27(Kip1)

An inverse correlation between p27(Kip1) expression and proliferation has b een recently established in tissues derived from human lymphomas. The nucle ophosminanaplastic lymphoma kinase (NPM-ALK)/phospholipase C-gamma (PLC gam ma) complex also appears to play an important role in cell proliferation an d malignant transformation of anaplastic large cell lymphoma (ALCL). In thi s study, we report that SUDHL-1 and KARPAS 299 ALCL-derived cell lines pres ent different sensitivity to the antiproliferative effect of recombinant ad enovirus-mediated p27(Kip1) expression or to serum-starvation in culture me dia. The results indicate that exogenous p27(Kip1) may interact with the NP M-ALK/ PLC;, pathway in SUDHL-1 but not in KARPAS 299 cells. This interacti on correlates with changes in cell cycle and cell morphology observed mainl y in SUDHL-1 cells. The percentage of SUDHL-1 cells in S phase declines, wh ereas it is almost unchanged in KARPAS 299 cells as compared to the control s after 96 h of infection with the recombinant adenovirus. Furthermore KARP AS 299 cells are resistant to serum-starvation due to deficient p27(Kip1)-u pregulation and G1 arrest, whereas SUDHL-1 cells respond with increased G1 phase and p27(Kip1)-upregulation after 48 h of serum-starvation. Both cell lines express appropriate variation of levels of cyclins E and A, and Rb-ph osphorylation as expected by growing them in culture media with different F BS content. Although both cell lines express cyclin D2, SUDHL-1 cells only present high level of cyclin D3. Moreover SUDHL-1 cells express high level of PTEN and the PKB/Akt pathway is constitutively activated in both cell li nes. Lastly SUDHL-1 cells show higher levels of phosphotyrosine-containing proteins that is correlated with a higher NPM-ALK-associated autophosphoryl ation activity compared to KARPAS 299 cells. Our study clearly identifies s ome of the biochemical differences that may explain the difference in sensi tivity to antiproliferative stimuli shown by two cell lines derived from th e same type of lymphoma.