We have previously shown that the disruption/deletion of the MTS(MTS1-MTS2) locus due to illegitimate V(D)J recombinase activity is a genetic event characteristic of T-cell acute lymphoblastic leukemia (T-ALL). Inactivation of the p16INK4a tumor suppressor protein, encoded by MTS1, is thought to be the major functional consequence of these chromosomal rearrangements. The two other cell cycle inhibitors encoded by genes identified in the locus (p19ARF by MTS1 and p15INK4b by MTS2), also represent possible candidates for inactivating events. By analyzing p16INK4a expression in three cases in which an identical 36-kb deletion had deleted MTS2 and disrupted the p19ARF, but spared the p16INK4a MTS1 encoding exons, we have excluded p16INK4a and pinpointed p19ARF and/or p15INK4b as the functional target(s) of this rearrangement. Moreover, by the study of the MTS genomic configuration of 149 rearranged alleles from a large series of T-ALL cases, we have shown that p19ARF encoding exons were always disrupted or deleted, whereas p16INK4a and p15INK4b encoding exons were spared in four and 21 cases, respectively. These results suggest that p19ARF may be targeted by the genetic events that occur in the MTS locus in the majority of T-ALLs.