|
|
Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-04-1010.
Submitted April 3, 2002
Accepted August 21, 2002
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
Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
* Corresponding author; email: herf1{at}hiroshima-u.ac.jp.
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, germline 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 long latency period. AML1 mutations were also 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% (2/74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA-binding potential and trans-activation activity. All missense mutations with one exception (G42R) lacked DNA-binding ability and downregulated the trans-activation potential of wild type AML1 in a dominant-negative fashion. The G42R mutation that was shared by two 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.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
V. Pullarkat, M. L. Slovak, A. Dagis, V. Bedell, G. Somlo, R. Nakamura, A. S. Stein, M. R. O'Donnell, A. Nademanee, A. L. Teotico, et al.
Acute leukemia and myelodysplasia after adjuvant chemotherapy for breast cancer: durable remissions after hematopoietic stem cell transplantation
Ann. Onc.,
December 1, 2009;
20(12):
2000 - 2006.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Miyazaki, N. Yamasaki, H. Oda, T. Kuwata, Y. Kanno, M. Miyazaki, Y. Komeno, J. Kitaura, Z.-i. Honda, S. Warming, et al.
Enhanced expression of p210BCR/ABL and aberrant expression of Zfp423/ZNF423 induce blast crisis of chronic myelogenous leukemia
Blood,
May 7, 2009;
113(19):
4702 - 4710.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-H. Kuo, S. K. Zaidi, S. Gornostaeva, T. Komori, G. S. Stein, and L. H. Castilla
Runx2 induces acute myeloid leukemia in cooperation with Cbf{beta}-SMMHC in mice
Blood,
April 2, 2009;
113(14):
3323 - 3332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Owen, C. L. Toze, A. Koochin, D. L. Forrest, C. A. Smith, J. M. Stevens, S. C. Jackson, M.-C. Poon, G. D. Sinclair, B. Leber, et al.
Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy
Blood,
December 1, 2008;
112(12):
4639 - 4645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Satoh, I. Matsumura, H. Tanaka, S. Ezoe, K. Fukushima, M. Tokunaga, M. Yasumi, H. Shibayama, M. Mizuki, T. Era, et al.
AML1/RUNX1 Works as a Negative Regulator of c-Mpl in Hematopoietic Stem Cells
J. Biol. Chem.,
October 31, 2008;
283(44):
30045 - 30056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Watanabe-Okochi, J. Kitaura, R. Ono, H. Harada, Y. Harada, Y. Komeno, H. Nakajima, T. Nosaka, T. Inaba, and T. Kitamura
AML1 mutations induced MDS and MDS/AML in a mouse BMT model
Blood,
April 15, 2008;
111(8):
4297 - 4308.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Dicker, C. Haferlach, W. Kern, T. Haferlach, and S. Schnittger
Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia
Blood,
August 15, 2007;
110(4):
1308 - 1316.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Cammenga, B. Niebuhr, S. Horn, U. Bergholz, G. Putz, F. Buchholz, J. Lohler, and C. Stocking
RUNX1 DNA-Binding Mutants, Associated with Minimally Differentiated Acute Myelogenous Leukemia, Disrupt Myeloid Differentiation
Cancer Res.,
January 15, 2007;
67(2):
537 - 545.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. P. Steensma and J. M. Bennett
The Myelodysplastic Syndromes: Diagnosis and Treatment
Mayo Clin. Proc.,
January 1, 2006;
81(1):
104 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. P. Steensma and A. F. List
Genetic Testing in the Myelodysplastic Syndromes: Molecular Insights Into Hematologic Diversity
Mayo Clin. Proc.,
May 1, 2005;
80(5):
681 - 698.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. C. Mulloy, V. Jankovic, M. Wunderlich, R. Delwel, J. Cammenga, O. Krejci, H. Zhao, P. J. M. Valk, B. Lowenberg, and S. D. Nimer
AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion
PNAS,
March 15, 2005;
102(11):
4016 - 4021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhang, J. R. Biggs, and A. S. Kraft
Phorbol Ester Treatment of K562 Cells Regulates the Transcriptional Activity of AML1c through Phosphorylation
J. Biol. Chem.,
December 17, 2004;
279(51):
53116 - 53125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. H. Christiansen, M. K. Andersen, and J. Pedersen-Bjergaard
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
Blood,
September 1, 2004;
104(5):
1474 - 1481.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Harada, Y. Harada, H. Niimi, T. Kyo, A. Kimura, and T. Inaba
High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia
Blood,
March 15, 2004;
103(6):
2316 - 2324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Ley, P. J. Minx, M. J. Walter, R. E. Ries, H. Sun, M. McLellan, J. F. DiPersio, D. C. Link, M. H. Tomasson, T. A. Graubert, et al.
A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes
PNAS,
November 25, 2003;
100(24):
14275 - 14280.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
