t(4;11) leukemias display addiction to MLL-AF4 but not to AF4-MLL.
The most frequent MLL-gene rearrangement found in leukemia is a reciprocal translocation with AF4 on chromosome 4 resulting in the formation of the MLL-AF4 and the AF4-MLL fusion genes. The oncogenic role of MLL-AF4 is documented but the significance of the reciprocal product - AF4-MLL in leukemia is less clear. In the human leukemia cell lines - RS4;11 and SEMK2-M1, both of which express MLL-AF4 and AF4-MLL, we knocked down the expression of AF4-MLL using siRNA. Loss of AF4-MLL had no effect on the growth of either RS4;11 or SEMK2-M1 cells. Furthermore, in SEMK2-M1 cells there were no changes in cell cycle or apoptosis with loss of AF4-MLL. In contrast, knockdown of MLL-AF4 significantly inhibited growth of both RS4;11 and SEMK2-M1. Additionally, in SEMK2-M1 cells, loss of MLL-AF4 led to G2/M cell cycle arrest and increased apoptosis. Overall, these results demonstrate that in t(4;11) leukemia, the MLL-AF4 fusion protein is critical for leukemia cell proliferation and survival while the AF4-MLL fusion product is dispensable.
Kumar
Ashish R
AR
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. ashish.kumar@cchmc.org
Yao
Qing
Q
Li
Quanzhi
Q
Sam
Thien A
TA
Kersey
John H
JH
D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D035602:Transcriptional Elongation Factors; D014178:Translocation, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C113855:MLL-AF4 fusion protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D011495:Histone-Lysine N-Methyltransferase