Overexpression of N-Myc Rapidly Causes Acute Myeloid Leukemia in Mice

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-Mycoverexpressing 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 B 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 f1 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]

The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes

“…Furthermore, previously reported data were obtained from patients with AML, rather than MDS, although up-regulation of TWIST has also been observed in AML. 55 In summary, the current studies present evidence for a role of TWIST in the pathophysiology of clonal myeloid diseases and provide data in patients with MDS, which offer new insights into stroma and hematopoietic cell interactions. The data also add to the complex picture of the pathophysiology of MDS.…”

Mcl1 haploinsufficiency protects mice from Myc-induced acute myeloid leukemia

“…Dysregulated Myc has been found in a large fraction of human cancers, and extensive studies have shed light on the mechanisms by which Myc overexpression promotes tumorigenesis (9)(10)(11)(12). Retrovirally mediated overexpression of C-Myc (13) or N-Myc (14) in mouse bone marrow cells rapidly induces an oligoclonal AML-like disease characterized by splenomegaly; accumulation of immature myeloid cells in bone marrow, spleen, thymus, and lymph nodes; hind limb paralysis; and death within 6 weeks. Myc induces AML in both C57BL/6 and Balb/c strains of mice with similar latency, and the leukemia is readily transplantable into secondary recipients (13).…”

Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis

“…In HPCs, MYCN produced a 3-fold rise in the concentration of the penultimate heme precursor, PPIX, but this was only revealed when ABCG2 was inhibited, suggesting that ABCG2 exported the excess protoporphyrin IX (PPIX) (Supplemental Figure 3B). ABCG2 is a MYCN transcriptional target in humans (12), and, in mice, MYCN also increased Abcg2 mRNA (Supplemental Figure 4) and also strongly increased the expression of ABCG2 protein ( Figure 3A). Although MYCN increased heme levels to a greater extent in ABCG2-KO HPCs, consistent with ABCG2's ability to export heme, we reasoned that loss of ABCG2, by disabling export of cytotoxic PPIX, might be deleterious to MYCN-overexpressing HPCs.…”

“…MYCN-transduced HPCs, after 3 serial replatings in methylcellulose culture (12), are capable of forming independent, phenotypically stable myeloid leukemia cell lines that produce a highly penetrant AML (12). However, it is unknown if mitochondrial respiration is crucial for MYCN to promote leukemic transformation.…”