Two critical hits for promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is associated with chromosomal translocations that always involve the RARα gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes). Due to the reciprocity of the translocation, X-RARα and RARα-X fusion proteins coexist in APL blasts. PLZF-RARα transgenic mice (TM) develop leukemia that lacks the differentiation block at the promyelocytic stage that characterizes APL. We generated TM expressing RARα-PLZF and PLZF-RARα in their promyelocytes. RARα-PLZF Tm do not develop leukemia. However, PLZF-RAR∅/RARα-PLZF double TM develop leukemia with classic APL features. We demonstrate that RARα-PLZF can interfere with PLZF transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RARα mutants and in PLZF-RARα/RARα-PLZF TM are indistinguishable. Thus, both products of a cancer-associated translocation are crucial in determining the distinctive features of the disease.