Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

Abstract

The basic helix -loop -helix factor E2A plays an important role in the development of B and T lymphocytes. In addition, E2a has been implicated as a gene with tumor suppressor activity, since mice deficient for E2a succumb to T cell lymphomas. We have performed retroviral tagging in EmMyc transgenic mice to identify genes that contribute to lymphomagenesis. The EmMyc transgenic mouse is a well-established model of a common translocation in human B cell lymphomas. Analyses of the proviral insertion sites in the MuLVinduced lymphomas revealed that a number of T cell lymphomas carried proviral insertions in the promoter region of E2a. These proviral insertions yield hybrid viral-E2a mRNAs resulting in a marked rise in E2A protein levels. The proviral insertions in E2a were predominantly of clonal origin indicating that E2a insertions are early events in these T cell lymphomas. The primary oncogenic effect of E2A is likely to be associated with enhancement of transcription of the cMyc transgene via binding to the regulatory immunoglobulin enhancers. The results herein thus provide the first evidence that in a specific setting E2A overexpression can contribute to T-lymphomagenesis. This implies that E2a contains oncogenic features in addition to the previously described tumor suppressive properties.

Ror γ ( Rorc ) Is a Common Integration Site in Type B Leukemogenic Virus-Induced T-Cell Lymphomas

“…Two recent studies using retroviral tagging identified the locus Sox4, encoding a transcription factor involved in B-and T-cell development, as a CIS for Moloney MuLV (25,31). Although Sox4 was the most frequently targeted CIS in the study by Suzuki et al (31) (55 of 194 tumors), we were unable to detect any TBLV integrations near Sox4.…”

“…Complementarity between these two genes was suggested by Winoto and Littman (35) and indicates the utility of using numerous genetic and viral models to examine oncogenic pathways since other large-scale retroviral tagging studies using MuLV failed to detect the Ror␥ locus as a CIS (19,25). Furthermore, 8.5% of the TBLVinduced tumors showed integrations in both c-myc and Ror␥ (Table 2).…”

“…Because retroviral integration is relatively random, identification of viral insertions within or near the same genes in different tumors suggests that there has been selection for outgrowth of cells carrying specific insertions. Such common integration sites (CISs) have been used as molecular tags to identify oncogenes, tumor suppressor genes, and oncogenic pathways (5,12,17,19,25,31). There are at least nine MMTV CISs, which generally fall into three categories (Wnt, Fgf, and Notch family genes [4,16,20,21,33]), whereas only two CISs, Tblvi1 and c-myc, have been described for TBLV.…”

Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas

“…However, newly developed PCR technologies and the mouse genome sequence databases allowed efficient high-throughput screening for retrovirally tagged genes. A large number of common insertion sites (CIS) in Moloney murine leukemia virus (M-MuLV)-induced lymphomas have recently been reported (Hwang et al, 2002;Lund et al, 2002;Mikkers et al, 2002a;Suzuki et al, 2002), highlighting the power of retroviral insertional mutagenesis. These developments urged us to start an exhaustive screening for novel oncogenes in MMTV-induced mouse mammary tumors.…”

Tal1 Transgenic Expression Reveals Absence of B Lymphocytes

“…Although Tal1 cannot form homodimers, it interacts and inhibits other helix-loop-helix factors such as E47/E2A and HEB (1,3). E47/E2A has been implicated as a gene with tumor suppressor activity because mice deficient for E2A succumb to T-cell lymphomas (4). A recent report showed that Tal1 induces T-ALL primarily by inhibiting transcriptional activity of E47 (3).…”