AML1-ETO and C-KIT mutation/overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec.
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.
Wang
Yue-Ying
YY
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.
Zhou
Guang-Biao
GB
Yin
Tong
T
Chen
Bing
B
Shi
Jing-Yi
JY
Liang
Wen-Xue
WX
Jin
Xiao-Long
XL
You
Jian-Hua
JH
Yang
Guang
G
Shen
Zhi-Xiang
ZX
Chen
Jue
J
Xiong
Shu-Min
SM
Chen
Guo-Qiang
GQ
Xu
Feng
F
Liu
Yi-Wei
YW
Chen
Zhu
Z
Chen
Sai-Juan
SJ
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
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