# DNA REARRANGEMENTS IN MOMULV-INDUCED THYMOMAS

> **NIH NIH R01** · FOX CHASE CANCER CENTER · 1993 · $226,447

## Abstract

The Tpl-2 locus. cloned by provirus tagging from a subline of the MoMuLV
induced rat thymoma 2769, defines a gene encoding a protein kinase which
is expressed primarily in spleen, thymus and lung. Tpl-2 spans a 35 kb
genomic DNA region and contains eight exons. During tumor progression
provirus insertion occurs in the last intron and in the same
transcriptional orientation with the Tpl-2 gene in 22.5% of the thymomas.
This leads to the enhanced expression of a truncated RNA transcript in
which the 3' exon is replaced by intron and proviral LTR sequences. This
transcript encodes a protein in which the 43 C-terminal amino acids
encoded by the eighth exon are replaced by seven amino acids encoded by
the last intron. This genetic change confers growth advantage to affected
cell clones. Cultivation of three sublines derived from tumor 2769,
selected cells which harbor independent provirus insertions in the Tpl-2
locus. One of these cell lines, upon continuing cultivation, underwent
further selection for cells expressing a short (2 kb) Tpl-2 mRNA
transcript, suggesting that the short RNA may encode a protein with
enhanced oncogenic activity. Given that rearrangements of the Tpl-2 locus
were frequently detected in primary tumors, we suggest that the selection
of cells with such rearrangements operates not only in culture but also in
vivo. Exposure of normal rat spleen cells to concanavalin A (ConA) induces
the expression of Tpl-2 within the first 60 minutes from the time of
exposure. This finding, which was observed both in the presence and
absence of cycloheximide, suggests that, in normal splenocytes, Tpl-2 may
be involved in the transition from a quiescent to the G1 phase of the cell
cycle. Tpl-2 is unique in that although it is a serine/threonine kinase,
it harbors an N-terminal domain exhibiting distant homology to the SH2
region of cytoplasmic tyrosine kinases. In vitro binding assays revealed
that the Tpl-2 SH2-like domain binds Src but falls to bind a kinase(-)
mutant of Src suggesting that binding may be phosphotyrosine dependent.
Proteins harboring the Tpl-2 type SH2-like domain are encoded by multiple
genes in all species from insects to mammals. A protein fragment that
extends between amino acids 1 and 290 was expressed in E. coli as a fusion
with the Maltose binding protein (MBP). After cleavage with activated
coagulation factor X, the Tpl-2 portion of the fusion protein was used to
raise polyclonal antibodies in rabbits. The antibodies detect a 55 kd
protein exhibiting kinase activity. Tpl-2 was mapped near the centromere
on rat chromosome 17, mouse chromosome 18 and human chromosome l0p11. The
Tpl-2 map location in humans defines a region characterized by karyotypic
abnormalities associated with adult T cell leukemia (ATL) and acute non-
lymphocytic leukemia (ANLL). The same region could also be involved in the
hereditary syndrome, multiple endocrine neoplasia type II.

## Key facts

- **NIH application ID:** 3176068
- **Project number:** 2R01CA038047-09A1
- **Recipient organization:** FOX CHASE CANCER CENTER
- **Principal Investigator:** PHILIP N. TSICHLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $226,447
- **Award type:** 2
- **Project period:** 1984-07-01 → 1996-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176068

## Citation

> US National Institutes of Health, RePORTER application 3176068, DNA REARRANGEMENTS IN MOMULV-INDUCED THYMOMAS (2R01CA038047-09A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176068. Licensed CC0.

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