Alterations in subnuclear trafficking of nuclear regulatory factors in acute leukemia

Abstract

The nuclear matrix plays an important role in the functional organization of the nucleus in part by locally concentrating regulatory factors involved in nucleic acid metabolism. A number of nuclear regulatory proteins initially identi®ed due to their involvement in human cancer are localized to discrete nuclear matrix-attached foci and correct nuclear partitioning likely plays a role in their function. Two such examples are promyelocytic leukemia (PML) and acute myelogenous leukemia-1 (AML-1; Runx1). PML, the target of the t(15;17) in acute PML, is localized to PML nuclear bodies (also termed Nuclear Domain 10 and PML oncogenic domains), a nuclear matrix-associated body whose function appears to be quite complex, with probable roles in cancer, apoptosis, and in acute viral infections. In t(15;17)-containing leukemic cells, the PML nuclear bodies are disrupted, but reform when the leukemic cells are induced to differentiate in the presence of all-trans retinoic acid. AML1 (RUNX1) is a key regulator of hematopoietic differentiation and AML1 proteins are found in nuclear compartments that re¯ect their roles in transcriptional activation and repression. The t(8;21), associated with AML, results in a chimeric transcription factor, AML-1/ETO (eight twenty one), that remains attached to the nuclear matrix through targeting signals contained in the ETO protein. When co-expressed, ETO and AML-1/ETO co-localize to a nuclear compartment distinct from that of AML1 or PML nuclear bodies. Interestingly, enforced expression of ETO or AML-1/ETO changes the average number of PML nuclear bodies per cell. Thus, chromosomal translocations involving AML1 result in altered nuclear traf®cking of the transcription factor as well as other changes to the nuclear architecture.In the past 30 years the view of the nucleus as composed of nucleoplasm and chromatin has evolved as ordered structures such as the nuclear matrix were identi®ed [Berezney and Coffey, 1974]. Advances in light and electron microscopy techniques, coupled with the localization of individual proteins has revealed that the nucleus is an organized structure and many nuclear proteins have speci®c sub-nuclear addresses [reviewed in Cardoso and Leonhardt, 1998;Lamond and Earnshaw, 1998]. The nuclear matrix, the non-chromatin nuclear scaffolding, is an integral player in the organization of structure and function in the nucleus performing regulatory roles in DNA replication, transcription, and RNA processing by locally concentrating regulatory factors [reviewed in Strouboulis and Wolffe, 1996;Cardoso and Leonhardt, 1998;Stein et al., 1999]. In cancerous cells, there are marked changes in the structure, size and internal organization of the nuclei [reviewed in Nickerson, 1998]. These changes may be the result of direct changes in the nuclear matrix and/or sub-nuclear localization of regulatory proteins. Because nucleic acid metabolism is organized through DNA and protein contacts with the nuclear matrix, disruption in nuclear architecture can affect the assembly of regulatory ...

RETRACTED ARTICLE: Genetic alterations of the NRP/B gene are associated with human brain tumors

“…Nuclear structural alterations are prevalent in cancer cells and commonly used as pathological markers of transformation in many types of cancer (Dardick et al, 1981;Getzenberg et al, 1996;Konety and Getzenberg, 1999;Davido and Getzenberg, 2000;Saunders et al, 2000;Brunagel et al, 2002). Furthermore, changes in the framework or composition of the nuclear structural framework may result in the transformation of normal cells to a malignant state by affecting transcription, replication, and/or other nuclear processes (Konety and Getzenberg, 1999;Alberti et al, 2000;Meyers and Hiebert, 2000;Stein et al, 2000;Brunagel et al, 2002). The discovery of a matrix constituent whose normal expression is neural specific may also offer a new area for brain research.…”

A T Lymphocyte-Specific Transcription Complex Containing RUNX1 Activates MHC Class I Expression

“…Two corepressors known to associate with RUNX1 bind to C-terminal regions: the transducin-like enhancer of split proteins, which are mammalian homologues of the Groucho family of corepressors, bind the C-terminal 5 residues (VWRPY) of RUNX1, whereas the corepressor mSin3A interacts with residues 208 -237 (39,43,53). A broad nuclear matrix targeting sequence and a transactivation domain also map to the C-terminal region and partially overlap the repression domains (77)(78)(79). As shown in Fig.…”

“…A number of translocation breakpoint products have been identified that block the normal function of the RUNX1/CBF␤ enhanceosome (27,68,87,88). The (8;21) translocation, found in ϳ10 -12% of acute myeloid leukemias, gives rise to AML1/ETO (new nomenclature: RUNX1-CBF2T1), consisting of the runt domain of RUNX1 in frame with almost the entire ETO gene (77,89). AML1/ETO knock-in mice, similar to RUNX1 Ϫ/Ϫ and CBF␤ Ϫ/Ϫ null transgenic mice, fail to develop any hemopoietic lineages and die in utero (90,91).…”

Subnuclear targeting of Runx/Cbfa/AML factors is essential for tissue-specific differentiation during embryonic development

“…Mutations in Runx factors that cause human disease also are associated with aberrations in subnuclear targeting (12,57,58). Leukemia-associated translocations in Runx1 that eliminate the C terminus result in altered transcriptional functions and subnuclear targeting (21,59).…”