A retrovirus carrying the promyelocyte-retinoic acid receptor PML-RAR alpha fusion gene transforms haematopoietic progenitors in vitro and induces acute leukaemias

The promyelocyte (PML)-retinoic acid receptor alpha (RAR alpha) fusion gene results from a t(15;17) chromosome translocation in acute promyelocytic leukaemia. We have analysed the oncogenic potential of the human fusion PML-RAR alpha product in chicken using retrovirus vectors. We show that PML-RAR alpha transforms very early haematopoietic progenitor cells in vitro and induces acute leukaemias. Neither PML nor RAR alpha domains alone achieve such a transformation. The PML-RAR alpha viruses recovered from the transformed cells carry two point mutations in the PML domain, one of which alters both the pattern of intracellular localization of the fusion protein and its functional interference with AP-1, thus defining an essential domain in PML for oncogenic transformation.