Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation.

The AML1 transcription factor is essential for normal hematopoiesis and is the target of several chromosomal translocations in acute leukemia. Acquired somatic AML1 mutations were recently demonstrated sporadically in de novo myelodysplasia (MDS) and acute myeloid leukemia (AML) including a few cases of therapy-related disease (t-MDS/t-AML). We examined 140 patients with t-MDS or t-AML for AML1 mutations by direct sequencing. We identified 9 missense, 3 nonsense, and 10 frameshift mutations, all heterozygous, in 22 patients (15.7%). Thirteen mutations were located in the N-terminal Runt homology domain (RHD), whereas 9 mutations were located in the C-terminal region including the transactivation domain (TAD). Nineteen patients with AML1 mutations had previously received alkylating agents whereas 2 patients had received radiotherapy only. AML1 mutations were highly significantly associated with presentation of the disease as t-MDS (P =.003), with deletion or loss of chromosome arm 7q (P =.001) and with subsequent transformation to overt t-AML (P =.0001). Patients with missense mutations presented a shorter survival compared with patients with nonsense/frameshift mutations (P =.03). Our results suggest that AML1 mutations and deletion of genes on chromosome arm 7q cooperate in leukemogenesis and predispose to leukemic transformation.