IgH enhancer deregulated expression of L-myc: abnormal T lymphocyte development and T cell lymphomagenesis.
Transgenic constructs containing the murine L-myc gene under the control of the immunoglobulin transcriptional enhancer element (Emu) are expressed at unexpectedly high levels in thymocytes and proliferating T cells compared with cells from bone marrow and proliferating B cells. In contrast, double transgenic animals bearing constructs containing the L- and N-myc genes similarly linked to the Emu element maintain preferential L-myc expression in T cells but express the N-myc transgene preferentially in B cells. These results indicate that the L-myc gene contains elements that act in concert with the Emu element to allow preferential expression in T lineage cells. In correspondence to the expression pattern, Emu-L-myc transgenic mice show expanded thymic cortices and irregularly formed splenic follicles with expanded T cell areas. Moreover, the percentage of thymocytes positive for the surface marker 1C11, which defines thymic progenitor cells, activated T cells and preleukemic T cells, is dramatically raised in transgenic mice compared with normal littermates. Emu-L-myc transgenic animals are predisposed to clonal lymphoid tumors, most of which are T cell lymphomas. The relative incidence, latency period, and degree of malignancy of Emu-L-myc tumors compared with Emu-N- or c-myc tumors is consistent with a lower oncogenic potential of the L-myc gene. However, the Emu-L-myc tumors do not express detectable levels of endogenous myc family genes indicating that the L-myc protein can substitute for c- or N-myc in the generation and growth of lymphoid neoplasms.
Möröy
T
T
Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Fisher
P
P
Guidos
C
C
Ma
A
A
Zimmerman
K
K
Tesfaye
A
A
DePinho
R
R
Weissman
I
I
Alt
F W
FW
D000818:Animals; D015152:Blotting, Northern; D002453:Cell Cycle; D002454:Cell Differentiation; D004273:DNA, Neoplasm / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005434:Flow Cytometry; D015870:Gene Expression; D005818:Genetic Engineering; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011519:Proto-Oncogenes; D012334:RNA, Neoplasm / Q000235:genetics; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000473:pathology
D004273:DNA, Neoplasm; D007143:Immunoglobulin Heavy Chains; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm