Intracisternal A-type particle-mediated activations of cytokine genes in a murine myelomonocytic leukemia: generation of functional cytokine mRNAs by retroviral splicing events.

Abstract

Previously we have described the derivation of three distinct classes of leukemic cell clones from a single in vivo-passaged myelomonocytic leukemia, , that arose in a mouse infected with the Abelson leukemia virus/Moloney leukemia virus complex (K. B. Leslie and J. W. Schrader, Mol. Cell. Biol. 9:2414Biol. 9: -2423Biol. 9: , 1989). The three classes of cell clones were characterized by distinct patterns of growth in vitro, the production of cytokines, and the presence of cytokine gene rearrangements. However, all three classes of WEHI-274 clones bore a common rearrangement of the c-myb gene, suggesting that all were derived from the one ancestral cell and that at least three distinct and independent autostimulatory events were involved in the progression of a single myeloid leukemic disease. In this article, we demonstrate that the autocrine growth factor production by the WEHI-274 leukemic clones resulted from cytokine gene activations mediated by the insertion of an intracisternal A-type particle (IAP) sequence 5' to the interleukin-3 (IL-3) gene, in the case of the class I clone, or 5' to the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF), in the case of the class II clones. IAPs are defective murine retroviruses encoded by endogenous genetic elements which may undergo transpositions and act as endogenous mutagens. The functional IL-3 and GM-CSF mRNAs were generated by mechanisms in which the splice donor apparatus of the IAP sequence has been used in IAP gag-to-IL-3 or -GM-CSF splicing events.

Unusual long target duplication by insertion of intracisternal A‐particle element in radiation‐induced acute myeloid leukemia cells in mouse

“…Similar integration events by IAP elements at different sites in the IL-3/GM-CSF locus were found in factor-independent sublines from several cell lines including D35 myeloid [4], FDC-P1 myeloid [5], WEHI-274 myeloid [6], PB-3c mast cell [7] and FL-5.12 lymphoid [8]. Because most of these sublines produce a large amount of IL-3 or GM-CSF mRNA, they are probably selected from IL-3/GM-CSF-dependent population with dominant phenotype of factor-independence.…”

“…4a, IAPR1) corresponding to the IAP element at antisense orientation and a backward primer (Fig. 4a, J 1 R) [6]; y, [7]; z, [8].…”

“…Additionally, an unusual long direct repeat of mouse DNA of 82 bp in length was generated at the insertion site of the lAP element, although the target duplication is no more than 6 bp in length in all the reported sequences suggesting a retroviral-like integration mechanism [3,5,6,8,[11][12][13][14][15][16][17][18][19]. The long target duplication may reflect a specific event which occurs during radiation-induced leukemogenesis.…”

“…Interestingly, integration of the IAP element into the interleukin (IL)-3/granulocyte macrophage colony-stimulating factor (GM-CSF) gene locus with gene activation has been found frequently in distinct tumor cell lines [3][4][5][6][7][8]. If the IL-3/GM-CSF locus has a tendency to accept lAP elements, several tumor cell *Corresponding author.…”

Characterization of Two Age-induced Intracisternal A-particle-related Transcripts in the Mouse Liver

“…The first splicing event may be described as a gag (nt 378)-to-env (nt 3413) splice, which is almost similar to the gag-to-env splicing event previously described in Ref. 24. In both cases, the same splice acceptor (SA1, Fig.…”