title: 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/RARalpha.
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 alpha (RARalpha) 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/RARalpha and we show that (a) the BTB/POZ domain mediates the oligomerization of PLZF/RARalpha; (b) mutations that inhibit dimerization of PLZF do the same in PLZF/RARalpha; (c) the PLZF/RARalpha-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/RARalpha-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/RARalpha-induced leukemogenesis.
authors: Department of Hematology, Johann Wolfgang Goethe-Universität, Frankfurt, Germany. puccetti@em.uni-frankfurt.de
authors: Elena
authors: E
authors: Puccetti
authors: Xiaomin
authors: X
authors: Zheng
authors: Daria
authors: D
authors: Brambilla
authors: Anita
authors: A
authors: Seshire
authors: Tim
authors: T
authors: Beissert
authors: Simone
authors: S
authors: Boehrer
authors: Heike
authors: H
authors: Nürnberger
authors: Dieter
authors: D
authors: Hoelzer
authors: Oliver Gerhard
authors: OG
authors: Ottmann
authors: Clara
authors: C
authors: Nervi
authors: Martin
authors: M
authors: Ruthardt
mesh_terms: D000208:Acute Disease; D000818:Animals; D019556:COS Cells; D019281:Dimerization; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D016335:Zinc Fingers
chemical_list: D056572:Histone Deacetylase Inhibitors; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; D006655:Histone Deacetylases