N. Yonedakato et al., THE T(3-5)(Q25.1-Q34) OF MYELODYSPLASTIC-SYNDROME AND ACUTE MYELOID-LEUKEMIA PRODUCES A NOVEL FUSION GENE, NPM-MLF1, Oncogene, 12(2), 1996, pp. 265-275
A t(3;5)(q25.1;q34) chromosomal translocation associated with myelodys
plastic syndrome and acute myeloid leukemia (AML) was found to rearran
ge part of the nucleophosmin (NPM) gene on chromosome 5 with sequences
from a novel gene on chromosome 3. Chimeric transcripts expressed by
these cells contain 5' NPM coding sequences fused in-frame to those of
the new gene, which we named myelodysplasia/myeloid leukemia factor 1
(MLF1). RNA-based polymerase chain reaction analysis revealed identic
al NPM-MLF1 mRNA fusions in each of the three t(3;5)-positive cases of
AML examined, The predicted MLF1 amino acid sequence lacked homology
to previously characterized proteins and did not contain known functio
nal motifs. Normal MLF1 transcripts were expressed in a variety of tis
sues, most abundantly in testis, ovary, skeletal muscle, heart, kidney
and colon. Anti-MLF1 antibodies detected the wild-type 31 kDa protein
in K562 and HEL erythroleukemia cell Lines, but not in HL-60, U937 or
KG-1 myeloid leukemia lines. By contrast, t(3;5)-positive leukemia ce
lls expressed a 54 kDa NPM-MLF1 protein, but not normal MLF1. Immunost
aining experiments indicated that MLF1 is normally located in the cyto
plasm, whereas NPM-MLF1 is targeted to the nucleus, with highest level
s in the nucleolus. The nuclear/nucleolar localization of NPM-MLF1 mir
rors that of NPM, indicating that NPM trafficking signals direct MLF1
to an inappropriate cellular compartment in myeloid leukemia cells.