Overexpression of N-Myc rapidly causes acute myeloid leukemia in mice

H Kawagoe, A Kandilci, TA Kranenburg, GC Grosveld - Cancer research, 2007 - AACR
H Kawagoe, A Kandilci, TA Kranenburg, GC Grosveld
Cancer research, 2007AACR
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 NH2-terminal transactivation domain,
nuclear localization signal, and bHLH/LZ domain of N-Myc are essential for this effect …
Abstract
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 NH2-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 β signaling and increased c-Jun-NH2-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 ∼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. [Cancer Res 2007;67(22):10677–85]
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