AML1-ETO and C-KIT Mutation/Overexpression in t(8;21) Leukemia: Implication in Stepwise Leukemogenesis and Response to Gleevec

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-01, Vol.102 (4), p.1104-1109
• Main Authors: Wang, Yue-Ying, Zhou, Guang-Biao, Yin, Tong, Chen, Bing, Shi, Jing-Yi, Liang, Wen-Xue, Jin, Xiao-Long, You, Jian-Hua, Yang, Guang, Shen, Zhi-Xiang, Chen, Jue, Xiong, Shu-Min, Chen, Guo-Qiang, Xu, Feng, Liu, Yi-Wei, Chen, Zhu, Chen, Sai-Juan
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Alleles; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Benzamides; Biological Sciences; Cell growth; Child; Child, Preschool; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit; Female; Gene expression; Genetic mutation; Genetics; Humans; Imatinib Mesylate; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Male; Medical genetics; Messenger RNA; Middle Aged; Mutation; Myeloid leukemia; Oncogene Proteins, Fusion - genetics; Piperazines - pharmacology; Pluripotent stem cells; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines - pharmacology; RUNX1 Translocation Partner 1 Protein; Stem cells; Transcription Factors - genetics; Translocation, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408831102

To explore the genetic abnormalities that cooperate with AML1-ETO (AE) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene (mC-KIT), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT, most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE, but not mC-KIT, could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT. Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.