The integrity of the charged pocket in the BTB/POZ domain is essential for the phenotype induced by the leukemia-associated t(11;17) fusion protein PLZF/RARα

Abstract

Acute myeloid leukemia is characterized by a differentiation block as well as by an increased self-renewal of hematopoietic precursors in the bone marrow. This phenotype is induced by specific acute myeloid leukemia-associated translocations, such as t(15;17) and t(11;17), which involve an identical portion of the retinoic acid receptor α (RARα) and either the promyelocytic leukemia (PML) or promyelocytic zinc finger (PLZF) genes, respectively. The resulting fusion proteins form high molecular weight complexes and aberrantly bind several histone deacetylase-recruiting nuclear corepressor complexes. The amino-terminal BTB/POZ domain is indispensable for the capacity of PLZF to form high molecular weight complexes. Here, we studied the role of dimerization and binding to histone deacetylase-recruiting nuclear corepressor complexes for the induction of the leukemic phenotype by PLZF/RARα and we show that (a) the BTB/POZ domain mediates the oligomerization of PLZF/RARα; (b) mutations that inhibit dimerization of PLZF do the same in PLZF/RARα; (c) the PLZF/RARα-related block of differentiation requires an intact BTB/POZ domain; (d) the mutations interfering with either folding of the BTB/ POZ domain or with its charged pocket prevent the self-renewal of PLZF/BARα-positive hematopoietic stem cells. Taken together, these data provide evidence that the dimerization capacity and the formation of a functionally charged pocket are indispensable for the PLZF/RARα-induced leukemogenesis. ©2005 American Association for Cancer Research.