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.

Puccetti, Elena, Zheng, Xiaomin, Brambilla, Daria, Seshire, Anita, Beissert, Tim, Boehrer, Simone, Nürnberger, Heike, Hoelzer, Dieter, Ottmann, Oliver Gerhard ORCID: https://orcid.org/0000-0001-9559-1330, Nervi, Clara and Ruthardt, Martin ORCID: https://orcid.org/0000-0003-1021-3811 2005. 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. Cancer Research 65 (14) , 6080–6088. 10.1158/0008-5472.CAN-04-3631

Full text not available from this repository.

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Date of Acceptance:	22 April 2005
Last Modified:	26 Feb 2024 12:30
URI:	https://orca.cardiff.ac.uk/id/eprint/166068

Actions (repository staff only)

Edit Item