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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1474-1481.
Prepublished online as a Blood First Edition Paper on May 13, 2004; DOI 10.1182/blood-2004-02-0754.
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Submitted March 1, 2004
Accepted April 22, 2004
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
Debes H Christiansen*, Mette K Andersen, and Jens Pedersen-Bjergaard
Department of Clinical Genetics, The Chromosome Laboratory, Section of Hematology/Oncology, Rigshospitalet, Copenhagen, Denmark
* Corresponding author; email: debes{at}rh.dk.
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 sporadic 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. Nine missense mutations, three nonsense and 10 frameshift mutations, all heterozygous, were identified in 22 patients (15.7%). Thirteen mutations were located in the N-terminal Runt homology domain (RHD) whereas nine mutations were located in the C-terminal region including the transactivation domain (TAD). Nineteen patients with AML1 mutations had previously received alkylating agents whereas two patients had received radiotherapy only. AML1 mutations were highly significantly associated with presentation of the disease as t-MDS (P = 0.003), with deletion or loss of chromosome arm 7q (P = 0.001) and with subsequent transformation to overt t-AML (P = 0.0001). Patients with missense mutations presented a shorter survival compared to patients with nonsense/frameshift mutations (P = 0.03). Our results suggest that AML1 mutations and deletion of genes on chromosome arm 7q cooperate in leukemogenesis and predispose to leukemic transformation.
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