High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21

The AML1 gene, situated in 21q22, is often rearranged in acute leukemias th rough t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gen e have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 p atients, including 131 with acute myeloid leukemia (AML), 94 with myelodysp lastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 wit h essential thrombocythemia (ET), Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 i n 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chrom osome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acq uired trisomy 21 (1 M1AML, 2 M2AML, 1 ET,and 1 atypical CML), In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had t he same missense or stop codon mutation in both AML1 alleles, which resulte d in at least 3 of the patients having duplication of the mutated allele an d deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagn osis and remission samples. In the remaining mutated cases, with acquired t risomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutatio ns were acquired in the leukemic clone. In conclusion, these findings confi rm the possibility of mutations of the Runt domain of the AML1 gene in leuk emias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21 . AML1 mutations, in MoAML, involved both alleles and probably lead to nonf unctional AML1 protein. As AML1 protein regulates the expression of the mye loperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869) (C) 20 00 by The American Society of Hematology.