Two critical hits for promyelocytic leukemia

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations that always involve the RAR alpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes). Due to the reciprocity of the translocation, X-RAR alpha and RAR alpha -X fusion proteins coexist in APL blasts. PLZF-RAR alpha transgenic mice (TM) develop leukemia that lacks the differentiation block at the promyelocytic stage that characterizes APL. We generated TM expressing RAR alpha -PLZF and PLZF-RAR alpha in 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 transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RAR alpha mutants and in PLZF-RAR alpha /RAR alpha -PLZF TM are indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.