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- Title
Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein.
- Authors
Yoneda-Kato, Noriko; Fukuhara, Shirou; Kato, Jun-ya
- Abstract
The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1-mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLF1 in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.
- Subjects
MOSAICISM; APOPTOSIS; MYELODYSPLASTIC syndromes; MYC proteins
- Publication
Oncogene, 1999, Vol 18, Issue 25, p3716
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1202711