Novel cryptic, complex rearrangements involving ETV6-CBFA2 (TEL-AMLI) genes identified by fluorescence in situ hybridization in pediatric patients with acute lymphoblastic leukemia

In, childhood B-lineage acute lymphoblastic leukemia (ALL), the most common genetic change, the ETV6-CBFA2 (TEL-AML1) fusion: resulting from the cryptic t(12;21)(p13;q22) is associated with a favorable outcome. Therefore, it is important to identify patients with this translocation so that they can receive appropriate treatment To identify new partner breakpoints for ETV6 and CBFA2, we selected 30 patients with childhood ALL in whose leukemic cells a t(12;21) had been detected by RT-PCR. Conventional cytogenetics revealed that 12p abnormalities were present in 10 patients and that other random abnormalities were present in another 15, including 9 with a numerical or structural abnormality of chromosome 21. Normal karyotypes were observed in the leukemic blasts of five patients. Interphase fluorescence in situ hybridization (FISH) confirmed the RT-PCR finding of the t(12;21) in each patient and detected the loss of the wild-type ETV6 allele in 14 (47%) patients. Metaphase cells from only 20 patients were available for additional FISH analysis. In 13 patients, the expected fusion signal of t(12;21) was observed on der(21)t(12;21), and the reciprocal CBFA2 signal was observed on der(12)t(12;21). However, in six patients with the ETV6-CSFA2 fusion on chromosome 21, the reciprocal CBFA2 signal was observed not on 12p 13 but on 4q21, 4q27, 8q24, 11q24, 14q11.2, or 16p13.1. In four of these six patients, we found interstitial insertions of part of CBFA2. In another patients the ETV6-CBFA2 fusion was observed on 4q21 rather than on 21q. Thus, seven (35%) of the 20 patients with a t(12;21) revealed complex rearrangements. Our findings also indicate the importance of analyzing metaphase chromosomes in identifying cryptic and complex rearrangements involving ETV6 and CBFA2. (C) 2001 Wiley-Liss, Inc.