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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-04-1010.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 673-680
NEOPLASIA
Implications of somatic mutations in the AML1 gene in
radiation-associated and therapy-related myelodysplastic syndrome/acute
myeloid leukemia
Hironori Harada,
Yuka Harada,
Hideo Tanaka,
Akiro Kimura, and
Toshiya Inaba
From the Department of Molecular Oncology and the
Department of Hematology/Oncology, Research Institute for Radiation
Biology and Medicine, Hiroshima University, Hiroshima,
Japan.
Somatically acquired point mutations of AML1/RUNX1 gene
have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations
of AML1 were found in an autosomal dominant disease, familial platelet
disorder with predisposition to AML (FPD/AML), suggesting that AML1
mutants, as well as AML1 chimeras, contribute to the transformation of
hematopoietic progenitors. In this report, we showed that AML1 point
mutations were found in 6 (46%) of 13 MDS patients among atomic bomb
(A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia
patients among A-bomb survivors, MDS patients exposed relatively
low-dose radiation and developed the disease after a long latency
period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating
agents with or without local radiation therapy. In contrast, frequency
of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among
AML1 mutations identified in this study, truncated-type mutants lost
DNA binding potential and trans-activation activity. All
missense mutations with one exception (Gly42Arg) lacked DNA
binding ability and down-regulated the trans-activation
potential of wild-type AML1 in a dominant-negative fashion. The
Gly42Arg mutation that was shared by 2 patients bound DNA even more
avidly than wild-type AML1 and enhanced the
trans-activation potential of normal AML1. These results
suggest that AML1 point mutations are related to low-dose radiation or
alkylating agents and play a role distinct from that of leukemogenic
chimeras as a result of chromosomal translocations caused by sublethal
radiation or topoisomerase II inhibitors.
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