Alterations in subnuclear trafficking of nuclear regulatory factors in acute leukemia

The nuclear matrix p lays an important role in the functional organization of the nucleus in part by local ly concentrating regulatory factors involve d in nucleic acid metabolism. A number of nuclear regulatory proteins initi ally identified due to their involvement in human cancer are localized to d iscrete nuclear matrix-attached foci and correct nuclear partitioning likel y plays a role in their function. Two such examples are promyelocytic leuke mia (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 term ed Nuclear Domain 10 and PML oncogenic domains), a nuclear matrix-associate d body whose function appears to be quite complex, with probable roles in c ancer, apoptosis, and in acute viral infections. In t(15;17)-containing leu kemic cells, the PML nuclear bodies are disrupted, but reform when the leuk emic cells are induced to differentiate in the presence of all-trans retino ic acid. AML1 (RUNX1) is a key regulator of hematopoietic differentiation a nd AML1 proteins are found in nuclear compartments that reflect 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 o ne), that remains attached to the nuclear matrix through targeting signals contained in the ETO protein. When co-expressed, ETO and AML-1/ETO co-local ize to a nuclear compartment distinct from that of AML1 or PML. nuclear bod ies. Interestingly, enforced expression of ETO or AML-1/ETO changes the ave rage number of PML nuclear bodies per cell. Thus, chromosomal translocation s involving AML1 result in altered nuclear trafficking of the transcription factor as well as other changes to the nuclear architecture. (C) 2001 Wile y-Liss, Inc.