Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia

• Published in: Blood Vol. 101; no. 2; pp. 673 - 680
• Main Authors: Harada, Hironori, Harada, Yuka, Tanaka, Hideo, Kimura, Akiro, Inaba, Toshiya
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.01.2003; The Americain Society of Hematology
• Subjects: Acute Disease; Adult; Aged; Aged, 80 and over; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; Case-Control Studies; Core Binding Factor Alpha 2 Subunit; DNA Mutational Analysis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Hematologic and hematopoietic diseases; Humans; Japan; Leukemia, Myeloid - etiology; Leukemia, Myeloid - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Myelodysplastic Syndromes - etiology; Myelodysplastic Syndromes - genetics; Neoplasms, Second Primary - genetics; Point Mutation - genetics; Protein Binding - genetics; Proto-Oncogene Proteins; Radiation Dosage; Radioactive Fallout - adverse effects; Transcription Factor AP-2; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Japan; Antineoplastic agent; Human; Secondary; Toxicity; Acute; Malignant hemopathy; Radiotherapy; Carcinogenesis; Genetic determinism; Myelodysplastic syndrome; Somatic mutation; Ionizing radiation; Complication; Genetics; Leukemogenesis; Acute myelocytic leukemia
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-04-1010

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 thetrans-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.