Genomic alterations of the p19ARF encoding exons in T-cell acute lymphoblastic leukemia

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 p16(INK4a) 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 (p19(ARF) by MTS1 and p15(INK4b) by MTS2), also represent possible candidates for inactivating events, By analyzing p16(INK4a) expression in three cases in which an identical 36-kb deletion had deleted MTS2 and disrupted the p19(ARF), but Spared the p16(INK4a) MTS1 encoding exons, we have excluded p16(INK4a) and pinpointed p19(ARF) and/or p15(INK4b) 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 p19(ARF) encoding exons were always disrupted or deleted, whereas p16(INK4a) and p15(INK4b) encoding exons were spared in four and 21 cases, respectively. These results suggest that p19(ARF) may be targeted by the genetic events that occur in the MTS locus in the majority of T-ALLs. (C) 1998 by The American Society of Hematology.