CBFA2(AML1) TRANSLOCATIONS WITH NOVEL PARTNER CHROMOSOMES IN MYELOID LEUKEMIAS - ASSOCIATION WITH PRIOR THERAPY

CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its prote in product forms the DNA-binding subunit of the heterodimeric core-bin ding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBF A2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in mye loid leukemia and with ETV6(TEL) in the t(12;21) common in childhood p re-B acute lymphoblastic leukemia, We have analyzed samples from 30 le ukemia patients who had chromosome rearrangements involving 21q22 by u sing fluorescence in situ hybridization (FISH). Our analysis showed th at 7 of them involved CBFA2 and new translocation partners. Two patien ts had a t(17;21)(q11.2;q22), whereas the other 5 had translocations i nvolving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel break points in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8:21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid diso rders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targ eting agents. The association of therapy-related disorders with transl ocations involving CBFA2 was significant by Fisher's exact test (P < . 003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhib itors. (C) 1998 by The American Society of Hematology.