The amino terminus of the mixed lineage leukemia protein (MLL) promotes cell cycle arrest and monocytic differentiation

Several lines of evidence suggest that the mixed lineage leukemia protein ( MLL, ALL-1, HRX) plays a role in regulating myelomonocytic differentiation. In this study we examined the effect of expression of MLL-AF9 on different iation of the monoblastic U937 cell line by using a tetracycline-inducible expression system. MLL-AF9 arrested growth of U937 cells and induced these cells to differentiate into macrophages; induction was accompanied by expre ssion of CD11b and CD14 and ultimately cell death. Deletion mutants of MLL- AF9 were used to map the sequences responsible for this effect. The amino-t erminal half of MLL was sufficient for both cell cycle arrest and macrophag e differentiation, whereas the carboxyl terminus of MLL or AF9 was found to be dispensable for this effect. Further deletions showed that a 35-kDa ami no-terminal fragment spanning two AT hook motifs was sufficient for cell cy cle arrest, up-regulation of p21(Cip1) and p27(Kip1), and partial different iation toward macrophages, These findings suggest a possible role far the M LL AT hook-containing region in regulating myelomonocytic differentiation.