Synergy between AUUUA Motif Disruption and Enhancer Insertion Results in Autocrine Transformation of Interleukin-3 - Dependent Hematopoietic Cells

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Abstract

Previously, we characterized the transposition of an intracisternal type A particle (IAP) to the 3′ untranslated region (UTR) of the interleukin-3 (IL-3) gene, which displaced two of the six AUUUA motifs associated with mRNA stability in an IL-3-secreting clone. To determine whether this rearrangement was involved in the autocrine transformation of the parental IL-3-dependent FL5.12 cell line, the germline (gIL-3) and rearranged IL-3 (rIL-3) genes were isolated and subcloned into a gene transfer vector. Moreover, the IAP-long terminal repeat (LTR) and the IL-3 3′UTR AUUUA motifs were deleted (rIL-3 + ΔLTR and gIL-3 + ΔAUUUA) in some IL-3 constructs to ascertain their role in the transformation process. The IAP-LTR was also added to these constructs (rIL-3 + ΔLTR + IAP-LTR, gIL-3 + ΔAUUUA + IAP-LTR, and gIL-3 + IAP-LTR), to determine whether it was necessary for autocrine transformation. The ability of the modified IL-3 genes to abrogate the IL-3 dependency of FL5.12 cells had the following rank order: rIL-3 was greater than rIL-3 + ΔLTR + IAP-LTR, which was greater than gIL-3 + ΔAUUUA + IAP-LTR, which was greater than gIL-3 + ΔAUUUA, which was equal to rIL-3 + ΔLTR, which was greater than gIL-3. The half-life of IL-3 mRIMA was 20-fold longer in cells containing a mutated as opposed to a wild-type AUUUA region. All of the factor-independent cells that expressed the IL-3 transgenes secreted IL-3 and were tumorigenic after injection into BALB/c nude mice. These results indicated that two events could synergize in the autocrine transformation of hematopoietic cells: (1) addition of a transcriptional enhancer present in a retroviral LTR, and (2) disruption of an mRNA stability region. © 1995 by The American Society of Hematology.

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Mayo, M. W., Wang, X. Y., Algate, P. A., Arana, G. F., Hoyle, P. E., Steelman, L. S., & McCubrey, J. A. (1995). Synergy between AUUUA Motif Disruption and Enhancer Insertion Results in Autocrine Transformation of Interleukin-3 - Dependent Hematopoietic Cells. Blood, 86(8), 3139–3150. https://doi.org/10.1182/blood.v86.8.3139.bloodjournal8683139

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