Acquisition of p16(INK4A) and p15(INK4B) gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia

Although numerous somatic mutations that contribute to the pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been identified, no speci fic cytogenetic or molecular abnormalities are known to be consistently ass ociated with relapse. The p16(INK4A) (p16), which encodes for both p16(INK4 A) and p19(ARF) proteins, and p15(INK4B) (P15) genes are inactivated by hom ozygous deletion and/or p15 promoter hypermethylation in a significant prop ortion of cases of childhood ALL at the time of initial diagnosis. To deter mine whether alterations in these genes play a role in disease progression, we analyzed a panel of 18 matched specimen pairs collected from children w ith ALL at the time of initial diagnosis and first bone marrow relapse for homozygous p16 and/or p15 deletions or p15 promoter hypermethylation. Four sample pairs contained homozygous p16 and p15 deletions at both diagnosis a nd relapse. Among the 14 pairs that were p16/p15 germline at diagnosis, thr ee ALLs developed homozygous deletions of both p16 and p15, and two develop ed homozygous p16 deletions and retained p15 germline status at relapse. In two patients, p15 promoter hypermethylation developed in the interval betw een initial diagnosis and relapse. In total, homozygous p16 deletions were present in nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases at relapse. These findings indicate that loss of function of proteins encoded by p16 and/or p 15 plays an important role in the biology of relapsed childhood ALL, and is associated with disease progression In a subset of cases. (C) 1999 by The American Society of Hematology.