TEL-AML1 translocations with TEL and CDKN2 inactivation in acute lymphoblastic leukemia cell lines

BNORMALITIES of the short arm of chromosome 12 A are relatively common in childhood acute lymphoblastic leukemia (ALL). Approximately 5% to 7% of children with ALL have cytogenetic evidence of a translocation involving 12p, whereas 3% to 5% have deletions that suggest the presence of a tumor-suppressor gene at this location.’ Through the use of sensitive molecular techniques, 12p or 12~12-13 loss of heterozygosity (LOH) has been shown in approximately 25% of childhood ALL cases.z4 Fluorescence in situ hybridization (FISH) mapping has detected a minimum region of overlap for the 12p deletions between the TEL. and CDKNIB (KIpl) genes.’ Recently, chromosomal translocations involving the TEL gene at 12~13 have been cloned in several hematopoietic In ALL cells with the t(12;21)(p13;q22), the 5’ part of TEL is fused with the AMLl gene.’.” Abnormalities of 12p, especially the t(12;21), are more reliably detected by FISH than by classical cytogenetics because the translocated portions of 12p and 21q are virtually identical cytogenetically.’* When FISH was combined with Southern blotting and reverse transcriptasepolymerase chain reaction (RT-PCR), the t(12;21) was identified as a recurring chromosomal abnormality in 16% to 25% of childhood B-lineage Despite the identification of the fusion partners in the t(12;21), the actual function of the TEL-AML1 and AMLl-TEL fusion proteins in promoting malignant transformation is unclear. Whether the TEL-AMLl fusion alone is necessary and sufficient for malignant transformation in ALL and whether TEL inactivation has a role in leukemogenesis is currently unknown. Loss of the CDKN2 (p16) gene at 9p21 is a common genetic abnormality in ALL and a variety of other malignancies. Homozygous CDKN2 deletions have been detected in approximately 15% of B-lineage ALL and 75% of T-lineage ALL The p16 protein functions as an inhibitor of cyclin-dependent kinase 4, and normally acts to stop cell cycle progres~ion.’~**~ Whether loss of p16 alone is necessary and sufficient for malignant transformation in childhood ALL has not been determined. In this report, 6 cell lines with the TEL-AMLl fusion transcript are described. Although only 1 of the 6 cell lines translocated allele of EL and 5 cell lines lacked expression of CDKN2. Moreover, in 2 patients (1 with the TEL-AMLI transcript and 1 without), EL exprwsion was lost with disease progression; ie, EL was expressed in the initial cell lines (established at diagnosis or first relapse) whereas 7Ef was not expressed in the cell lines established from these patients in late-stage disease. These data show the coexistence of multiple genetic defects in childhood B-lineage ALL. Cell lines with t(12;21) will faciliate the study of TEL-AML1 and AMLl-TEL fusion proteins as well as EL and CDKM gene inactivation in leukemia transformation and progression.