title: AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.
abstract: 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.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Department of Medical Laboratory Science, Ruijin Medical College, Rui Jin Hospital Affiliated to Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China.
authors.forename: Yue-Ying
authors.initials: YY
authors.lastname: Wang
authors.forename: Guang-Biao
authors.initials: GB
authors.lastname: Zhou
authors.forename: Tong
authors.initials: T
authors.lastname: Yin
authors.forename: Bing
authors.initials: B
authors.lastname: Chen
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Shi
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Liang
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Jin
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: You
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.forename: Jue
authors.initials: J
authors.lastname: Chen
authors.forename: Shu-Min
authors.initials: SM
authors.lastname: Xiong
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Liu
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D000970:Antineoplastic Agents; D001549:Benzamides; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit