Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice.
N-MYC encodes a basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that is frequently overexpressed in human neuroblastoma. N-MYC overexpression has also been reported in human acute myeloid leukemias (AML), which we show here is a frequent event. Myeloid cells in N-Myc-overexpressing mouse bone marrow hyperproliferate but those in c-MYC-overexpressing bone marrow do not. The NH(2)-terminal transactivation domain, nuclear localization signal, and bHLH/LZ domain of N-Myc are essential for this effect. Microarray analysis revealed 969 differentially expressed genes between N-Myc- and c-MYC-overexpressing myeloid cells. N-Myc-overexpressing cells showed decreased transforming growth factor beta signaling and increased c-Jun-NH(2)-kinase signaling, both of which are associated with proliferation and leukemic transformation of myeloid cells. Mice transplanted with bone marrow expressing wild-type N-Myc developed clonal and transplantable AML after approximately 1 month; those transplanted with bone marrow expressing mutant N-Myc did not. Twist, a known suppressor of the p19Arf/p53 pathway, was up-regulated in all tumors. These results show that N-Myc overexpression is highly oncogenic in mouse myeloid cells and suggest that N-MYC up-regulation contributes to human myeloid leukemogenesis.
Kawagoe
Hiroyuki
H
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Kandilci
Ayten
A
Kranenburg
Tanya A
TA
Grosveld
Gerard C
GC
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic; D015973:Gene Expression Regulation, Leukemic; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; D048031:JNK Mitogen-Activated Protein Kinases