Two critical hits for promyelocytic leukemia

Acute promyelocytic leukemia (APL) is associated with chromosomal transloca tions that always involve the RAR alpha gene, which variably fuses to one o f several distinct loci, including PML or PLZF (X genes). Due to the recipr ocity of the translocation, X-RAR alpha and RAR alpha -X fusion proteins co exist in APL blasts. PLZF-RAR alpha transgenic mice (TM) develop leukemia t hat lacks the differentiation block at the promyelocytic stage that charact erizes APL. We generated TM expressing RAR alpha -PLZF and PLZF-RAR alpha i n their promyelocytes. RAR alpha -PUF TM do not develop leukemia. However, PLZF-RAR alpha /RAR alpha -PLZF double TM develop leukemia with classic APL features. We demonstrate that RAR alpha -PLZF can interfere with PLZF tran scriptional repression and that this is critical for APL pathogenesis, sinc e leukemias in PLZF(-/-)/PLZF-RAR alpha mutants and in PLZF-RAR alpha /RAR alpha -PLZF TM are indistinguishable. Thus, both products of a cancer-assoc iated translocation are crucial in determining the distinctive features of the disease.