MYC levels govern hematopoietic tumor type and latency in transgenic mice.
Deregulated MYC expression has been implicated in the etiology of many human cancers, including hematopoietic malignancies. To explore the impact of widespread constitutive MYC expression in the hematopoietic compartment, we have used a vector containing regulatory elements of the Vav gene to generate transgenic mice. VavP-MYC mice are highly tumor-prone and the level of MYC was found to influence both the kinetics and nature of the malignancies that developed. Whereas aggressive T-cell lymphomas rapidly overwhelmed the highest-expressing line, late-onset monocytic tumors greatly predominated in 2 low-expressing lines. These monocytic tumors most likely arise from abnormal macrophage colony-stimulating factor (M-CSF)-dependent progenitor cells having enhanced self-generative capacity. There appears to be a sharp threshold for MYC-induced T-cell lymphomagenesis because merely doubling the MYC level in a low-expressing line by breeding homozygous transgenic animals switched the phenotype from primarily monocytic tumors to exclusively T-cell tumors. Even the low level of MYC, however, clearly affected T-cell cycling, size, and sensitivity to apoptosis, and coexpression of a BCL2 transgene promoted efficient T-cell lymphomagenesis. The implication is that MYC level affects the spontaneous acquisition of synergistic oncogenic mutations.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Darrin P
DP
Smith
Mary L
ML
Bath
Donald
D
Metcalf
Alan W
AW
Harris
Suzanne
S
Cory
D000818:Animals; D019337:Hematologic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics; D013601:T-Lymphocytes / Q000473:pathology
C489427:MYC protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051567:Proto-Oncogene Proteins c-vav; C052617:Bcl2 protein, mouse; D016173:Macrophage Colony-Stimulating Factor