title: The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell.
abstract: The cellular properties of leukemia stem cells (LSCs) are achieved at least through Class I and Class II mutations that generate signals for enhanced proliferation and impaired differentiation, respectively. Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities. Six t(8;21) AML patients with c-KIT mutants maintaining > 3 years of complete remission were analyzed. At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. However, in remission, 16 out of 1,728 CD34(+)CD38(-) HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. Microarray analysis suggested that mutated c-KIT signaling provides LSCs with enhanced survival and proliferation. Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs.
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan; Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shima
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Yoshikane
authors.initials: Y
authors.lastname: Kikushige
authors.affiliation: Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yuda
authors.affiliation: Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Tochigi
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Goichi
authors.initials: G
authors.lastname: Yoshimoto
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Cancer Research Institute of Kanazawa University, Ishikawa, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Goto
authors.affiliation: Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan; Center for Cellular and Molecular Medicine, Graduate School of Medical Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan. Electronic address: akashi@med.kyushu-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit