The RARα-PLZF chimera associated with Acute Promyelocytic Leukemia has retained a sequence-specific DNA-binding domain

Abstract

In most cases, Acute Promyelocytic Leukemia (APL) is associated with t(15;17) translocation which juxtaposes sequences from PML and retinoic acid receptor α (RARα) genes. The generated PML-RARα fusion interferes with wild type RARα-mediated transcription and disrupts subnuclear compartments, known as PML bodies. Both defects are corrected by all trans retinoic acid (ATRA) therapy which induces differentiation of leukemic cells and clinical remission. In a rare APL syndrome associated with t(11;17), fusion of the RARα gene with the PLZF gene, encoding a Zinc-finger protein produces two reciprocal RARα chimeras. Although PLZF-RARα and PML-RARα are similar in their apparent dominant negative effects, t(11;17)-associated APL is refractory to ATRA therapy. In a yeast two-hybrid genetic screening, we isolated clones encoding the GAL4 transactivation domain fused to various parts of PLZF. Using these autonomously transactivating hybrids, similar in structure to the RARα-PLZF fusion, we mapped the DNA-binding domain of PLZF to the last five Zinc-fingers, a region retained in RARα-PLZF chimera and characterized a specific PLZF target sequence. Our data support the hypothesis that RARα-PLZF chimera is not an inert product of reciprocal translocation and may thus contribute to ATRA unresponsiveness of t(11;17)-associated APL.