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Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8-
lymphocytes in the thymus and T-cell tumors in transgenic mice
GA Neale, JE Rehg and RM Goorha
Department of Virology and Molecular Biology, St. Jude Children's Research
Hospital, Memphis 38101, USA.
Although the proto-oncogene rhombotin-2 (RBTN-2) is widely expressed in
most tissues, it is not expressed in T cells. We investigated the potential
for overexpression of RBTN-2 to cause tumors in T cells and other tissues
by constructing transgenic mice that expressed RBTN-2 under control of the
metallothionein-1 promoter. Despite overexpression of RBTN-2 in all
tissues, transgenic mice developed T-cell tumors only, thus indicating that
tumorigenesis caused by RBTN-2 is T-cell-specific. Thymic tumors were found
between 37 and 71 weeks and were invariably associated with metastasis to
nonlymphoid organs. Thymuses from apparently healthy transgenic mice were
also examined. In some mice there was an 10-fold increase in the CD4-CD8-
thymocyte subset, yet the total number of thymocytes was the same as that
in wild-type mice. Thymic homeostasis was maintained by a compensatory
reduction in the CD4+CD8+ subset. The expansion of CD4-CD8- thymocytes was
associated with increased expression of RBTN-2 and with increased cell
proliferation. No differences were found in the proportion of thymocytes
undergoing apoptosis in transgenic mice. Furthermore, RBTN-2- induced
expansion of CD4-CD8- cells did not block differentiation of these cells.
Thymuses with 30% CD4-CD8- cells were essentially monoclonal, indicating
that all thymic immunophenotypes were derived from a single clone. Overall,
our data are consistent with the following scenario: (1) RBTN-2 expression
in T cells causes selective and polyclonal proliferation of CD4-CD8-
thymocytes accompanied by a compensatory decrease in other thymocyte
subsets; (2) a clone with growth advantage and differentiation potential is
selected and populates the thymus; and (3) this clone eventually breaches
homeostasis of the thymus, accompanied or followed by metastasis to other
organs.
Volume 86,
Issue 8,
pp. 3060-3071,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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