Reversibility of acute B-cell leukaemia induced by BCR-ABL1

Cancer is thought to arise from multiple genetic events that establish irre versible malignancy. A different mechanism might be present in certain leuk aemias initiated by a chromosomal translocation. We have taken a new approa ch to determine if ablation of the genetic abnormality is sufficient for re version by generating a conditional transgenic model of BCR-ABL1 (also know n as BCR-ABL)-induced leukaemia. This oncogene(1) is the of a reciprocal tr anslocation and is associated with differ-ent forms of leukaemia(2). The mo st common form, p210 BCR-ABL1, is found in more than 90% of patients with c hronic myelogenous leukaemia(3,4) (CML) and in up to 15% of adult patients with de novo acute lymphoblastic leukaemia(5) (ALL). Efforts to establish a useful transgenic model have been hampered by embryonic lethality when the oncogene is expressed during embryogenesis(6,7), by reduced penetrance or by extremely long latency periods(8,9). One model uses the 'knock-in' appro ach to induce leukaemia by p190 BCR-ABL1 (ref. 10). Given the limitations o f models with p210, we used a different experimental approach(11) Lethal le ukaemia developed within an acceptable time frame in all animals, and compl ete remission was achieved by suppression of BCR-ABL1 expression, even afte r multiple rounds of induction and reversion. Our results demonstrate that BCR-ABL1 is required for both induction and maintenance of leukaemia.