Different patterns of homozygous p16INK4A and p15INK4B deletions in childhood acute lymphoblastic leukemias containing distinct E2A translocations.

The p16INK4A (p16) and p15INK4B (p15) tumor suppressor genes are inactivated by homozygous gene deletion and p15 promoter hypermethylation in a significant proportion of childhood acute lymphoblastic leukemias (ALLs). However, little is known about the potential association between p16/p15 gene alterations and specific genetic abnormalities implicated in leukemogenesis. The t(1;19)(q23;p13) and t(17;19)(q21-22;p13) are non-random translocations observed in childhood ALL that create distinct E2A fusion proteins: E2A-PBX1 and E2A-HLF, respectively. Previously, a negative association was found between the t(1;19) and homozygous p16/p15 deletions. In this study we determined p16 and p15 gene status in additional t(1;19)+ ALLs and compared this incidence to that observed in t(17;19)+ ALLs. No homozygous p16 or p15 deletions were observed among 13 t(1;19)+ ALLs analyzed. In contrast, homozygous deletions of both p16 and p15 were present in two of four t(17;19)+ ALLs. None of 10 t(1;19)+ ALLs contained p15 promoter hypermethylation. In contrast, one of the two t(17;19)+ ALLs that lacked p15/p16 homozygous deletions showed probable hemizygous p15 hypermethylation. We conclude that homozygous p16 and/or p15 deletions and p15 hypermethylation rarely accompany E2A-PBX1 fusion, but occur in concert with E2A-HLF fusion in a subset of t(17;19)+ ALLs. These findings suggest that there may be different modes of cooperative leukemogenesis in ALLs associated with different E2A fusion proteins.