Inhibition of P210 Expression in Chronic Myeloid Leukaemia: Oligonucleotides and/or Transduced Antisense Sequences

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Abstract
There is now strong evidence that the BCR-ABL gene product (P210) of the Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukaemia (CML). That is why antisense strategies aiming at inhibiting P210 expression for research or therapeutic purposes are increasingly investigated. Two main tools are currently available in this respect: oligonucleotides and retrovirally transduced antisense sequences. In this paper, we discuss the potential advantages and drawbacks of each approaches and report experimental evidences showing the feasibility of the second one in a murine lymphoid cell line (BaF3) expressing P210 upon retroviral transduction of the complete BCR-ABL cDNA. A retroviral vector was used to introduce selected antisense and sense sequences into this cell line, that P210 expression had rendered Interleukin-3 (IL3) independent. The antisense transcripts generated under the control of MoMLV promoter specifically killed BaF3 cells in the absence of IL3 and stably inhibited P210 expression. Retrovirally transduced antisense sequences can thus successfully achieve stable suppression of P210 and may be used to study further the mechanisms by which P210 is transforming cells. The effect on CML cell lines and fresh CML cells, in bone marrow cultures, remains to be investigated before considering this technique for in vitro selective suppression of Philadelphia-positive haematopoiesis.