F-MuLV acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4

Abstract

We describe here the development of a murine system for the identification of genes involved in myelomonocytic neoplasms. Transgenic C57BL/6J mice expressing SV40 early region under a myelomonocytic promoter develop histiocytic sarcomas with a latency of 167 days. We used retroviral proviral tagging to accelerate tumorigenesis and to uncover genetic changes that contribute to tumor development. Infection of transgenic mice with Friend murine leukemia virus (F-MuLV) shortened the latency of morbidity to 103 days (P Ͻ 0.001); this was associated with clonal proviral integrations in tumor DNA. As expected for F-MuLV, proviral insertions occurred at Fli1 in both transgenic and nontransgenic tumors. Four insertions were found at a novel locus, termed Fim4, on chromosome 6. This region is syntenic to human 7q32, a region that is commonly deleted in human myelodysplastic syndrome and acute myeloid leukemia. A murine BAC containing Fim4 was sequenced and analyzed, and while there was significant human-mouse homology in the area of the insertions, no candidate gene has been identified. Thus we have established a system to identify genes involved in myelomonocytic tumors, and have used it to identify Fim4, a new common site of proviral insertion. Study of this locus may provide insight into genes involved in AML-associated 7q32 deletions in humans.

Assessment of F-MuLV-induced tumorigenesis reveals new candidate tumor genes including Pecam1, St7, and Prim2

“…The short variant is differed from long form by 39 base pairs, that reflects the loss of the exon 2 of Aml1 gene during rearrangement or in the process of alternative splicing. 1 It is known that various splice-variants/transcripts of fusion genes can be associated with different clinical features. For example, leukemic clone expressing Bcr-Abl p210 is more responsive to Gleevec therapy comparing with Bcr-Abl p190 positive cells.…”

“…High-molecular-weight DNA was extracted from frozen spleen tumors and inverse PCR was performed as described (1). PCR products from the secondary PCR reaction were cloned into pAMP1-cloning vector (Gibco BRL).…”

“…Tumors were generated as described 1 . Tumors were diagnosed by histopathologic examination of H+E-stained spleen, liver, bone marrow and lymph nodes.…”

Clonal proliferation of HTLV-1-infected cells is associated with spontaneous malignant tumor formation in mice

“…It is well established that clonal growth of MuLV-infected cells results from insertional mutagenesis through integration in or around various growthrelated genes (15,16). A similar mechanism was recently proposed for ATL (17,18).…”

Insertional Mutagenesis by Replication‐Deficient Retroviral Vectors Encoding the Large T Oncogene

“…A number of complementation studies have revealed that genes belonging to mitotic and antiapoptotic pathways are powerful cooperation partners in the clonal evolution of TAg‐associated tumors. Well‐studied examples are (proto‐)oncogenic receptors, such as Csfr1=c‐Fms, 15 signal transducers, such as Ras 15,16 or Src, 15 transcription factors, such as Fli1, 17 and apoptosis modulators, such as Bcl2. 18 Moreover, it has been shown that TAg acts as a chaperone, collaborating with cellular heat shock proteins ( Hsp ) 11 …”