INHIBITION OF P210 EXPRESSION IN CHRONIC MYELOID-LEUKEMIA - OLIGONUCLEOTIDES AND OR TRANSDUCED ANTISENSE SEQUENCES

There is now strong evidence that the BCR-ABL gene product (P210) of t he Philadelphia chromosome plays a crucial role in the pathogenesis of chronic myeloid leukaemia (CML). That is why antisense strategies aim ing 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 antisen se sequences. In this paper, we discuss the potential advantages and d rawbacks 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 an d sense sequences into this cell line, that P210 expression had render ed Interleukin-3 (IL3) independent. The antisense transcripts generate d under the control of MoMLV promoter specifically killed BaF3 cells i n the absence of IL3 and stably inhibited P210 expression. Retrovirall y 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 fr esh CML cells, in bone marrow cultures, remains to be investigated bef ore considering this technique for in vitro selective suppression of P hiladelphia-positive haematopoiesis.