Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2 alpha B gene associated with myeloblastic leukemias

The AML1 gene encoding the DNA-binding alpha-subunit in the Runt domain fam ily of heterodimeric transcription factors has been noted for its frequent involvement in chromosomal translocations associated with leukemia. Using r everse transcriptase-polymerase chain reaction (RT-PCR) combined with nonis otopic RNase cleavage assay (NIRCA), we found point mutations of the AML1 g ene in 8 of 160 leukemia patients: silent mutations, heterozygous missense mutations, and biallelic nonsense or frameshift mutations in 2, 4, and 2 ca ses, respectively. The mutations were all clustered within the punt domain. Missense mutations identified in 3 patients showed neither DNA binding nor transactivation, although being active in heterodimerization. These defect ive missense mutants may be relevant to the predisposition or progression o f leukemia. On the other hand, the biallelic nonsense mutants encoding trun cated AML1 proteins lost almost all functions examined and may play a role in leukemogenesis leading to acute myeloblastic leukemia. (C) 1999 by The A merican Society of Hematology.