The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell

Takahiro Shima, Toshihiro Miyamoto, Yoshikane Kikushige, Junichiro Yuda, Taro Tochigi, Goichi Yoshimoto, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Shinichi Mizuno, Noriko Goto, Koichi Akashi

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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>3years 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.

Original languageEnglish
Pages (from-to)955-965.e5
JournalExperimental Hematology
Volume42
Issue number11
DOIs
Publication statusPublished - Nov 1 2014

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Acute Myeloid Leukemia
Stem Cells
Leukemia
Mutation
Hematopoietic Stem Cells
Microarray Analysis
Blood Cells
Up-Regulation
Survival

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell. / Shima, Takahiro; Miyamoto, Toshihiro; Kikushige, Yoshikane; Yuda, Junichiro; Tochigi, Taro; Yoshimoto, Goichi; Kato, Koji; Takenaka, Katsuto; Iwasaki, Hiromi; Mizuno, Shinichi; Goto, Noriko; Akashi, Koichi.

In: Experimental Hematology, Vol. 42, No. 11, 01.11.2014, p. 955-965.e5.

Research output: Contribution to journalArticle

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