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 genera...

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Veröffentlicht in:Blood 2006-07, Vol.108 (2), p.653-661
Hauptverfasser: Smith, Darrin P., Bath, Mary L., Metcalf, Donald, Harris, Alan W., Cory, Suzanne
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container_issue 2
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container_title Blood
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creator Smith, Darrin P.
Bath, Mary L.
Metcalf, Donald
Harris, Alan W.
Cory, Suzanne
description 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.
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subjects Animals
Hematologic Neoplasms - etiology
Hematologic Neoplasms - genetics
Hematologic Neoplasms - pathology
Hematopoietic Stem Cells - pathology
Humans
Leukemia, Myeloid - etiology
Leukemia, Myeloid - pathology
Lymphoma, T-Cell - etiology
Lymphoma, T-Cell - pathology
Macrophage Colony-Stimulating Factor - pharmacology
Mice
Mice, Transgenic
Mutation
Neoplasia
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins c-bcl-2
Proto-Oncogene Proteins c-myc - analysis
Proto-Oncogene Proteins c-myc - physiology
Proto-Oncogene Proteins c-vav - genetics
T-Lymphocytes - pathology
title MYC levels govern hematopoietic tumor type and latency in transgenic mice
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