The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

The t(8;21) chromosomal translocation in acute myelogenous leukemia modifies intranuclear targeting of the AML1/CBFα2 transcription factor

^*Department of Cell Biology and Cancer Center, University of Massachusetts, Medical School, 55 Lake Avenue North, Worcester, MA 01655; and ^‡Department of Biochemistry, Vanderbilt University School of Medicine, Medical Research Building II, Room 512, 21st and Garland, Nashville, TN 37232-0146

Communicated by Sheldon Penman, Massachusetts Institute of Technology, Cambridge, MA (received for review September 1, 1999)

Abstract

Targeting of gene regulatory factors to specific intranuclear sites may be critical for the accurate control of gene expression. The acute myelogenous leukemia 8;21 (AML1/ETO) fusion protein is encoded by a rearranged gene created by the ETO chromosomal translocation. This protein lacks the nuclear matrix-targeting signal that directs the AML1 protein to appropriate gene regulatory sites within the nucleus. Here we report that substitution of the chromosome 8-derived ETO protein for the multifunctional C terminus of AML1 precludes targeting of the factor to AML1 subnuclear domains. Instead, the AML1/ETO fusion protein is redirected by the ETO component to alternate nuclear matrix-associated foci. Our results link the ETO chromosomal translocation in AML with modifications in the intranuclear trafficking of the key hematopoietic regulatory factor, AML1. We conclude that misrouting of gene regulatory factors as a consequence of chromosomal translocations is an important characteristic of acute leukemias.

Footnotes

↵ † Present address: IntraImmune Therapies Incorporated, 2127 Burlington Avenue, Boston, MA 02011.
↵ § To whom reprint requests should be addressed.
Abbreviations:

AML,

acute myelogenous leukemia;

ETO,

eight;

twenty one protein,

NMTS, nuclear matrix-targeting signal;

NM-IF,

nuclear matrix–intermediate filament;

HA,

hemagglutinin;

EGFP,

enhanced green fluorescent protein