SPECIFIC DELETION IN THE BREAKPOINT CLUSTER REGION OF THE ALL-1 GENE IS ASSOCIATED WITH ACUTE LYMPHOBLASTIC T-CELL LEUKEMIAS

A variety of chromosomal translocations to the ALL-1 gene are regularl y observed in acute leukemias and are thought to play a key role in th e leukemogenic process, Chimeric proteins encoded by the breakpoint re gions of the derivative chromosomes have been proposed to be the relev ant oncogenic agents, In addition, internal duplications of the ALL-1 gene have been observed in patients with specific acute myeloid leukem ias, Thus, it has been hypothesized that oncogenic variants of the ALL -1 protein may be generated by both chimerization and self-fusion, but the critical structural features endowing the altered proteins with t heir oncogenic potential are still unknown, Here a novel structural al teration of the ALL-1 gene was observed in three patients presenting w ith acute T-cell leukemia (ALL) without chromosomal translocations or self-fusions of the ALL-1 gene, These unrelated patients carried an in ternal deletion in one of the two alleles of the ALL-1 gene that elimi nated parts of introns 7 and 8, together with exon 8, The deletion was found in 3 of 74 ALL patients, but not in acute myeloid leukemias, fo llicular lymphomas, or peripheral blood leukocytes from healthy donors , One ALL patient showed the deletion at diagnosis but no longer at re mission or at 9 months after remission, These findings support the hyp othesis that the ALL-1 protein may be converted to an oncogenic varian t, not only by chimerization or self-fusion, but also by deletion of s equences coded by exon 8, They further suggest that these three differ ent types of structural alterations of the ALL-1 protein may each caus e a distinct disease phenotype, Alternatively spliced mRNA species omi tting exon 8 mere observed in 14 of 24 ALL patients without detectable macroscopic alterations of the ALL-1 gene and also in peripheral bloo d leukocytes from healthy donors.