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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4514-4523.
Prepublished online as a Blood First Edition Paper on February 2, 2006; DOI 10.1182/blood-2005-11-4745.
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NEOPLASIA
Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML
Brunangelo Falini,
Niccolò Bolli,
Jing Shan,
Maria Paola Martelli,
Arcangelo Liso,
Alessandra Pucciarini,
Barbara Bigerna,
Laura Pasqualucci,
Roberta Mannucci,
Roberto Rosati,
Paolo Gorello,
Daniela Diverio,
Giovanni Roti,
Enrico Tiacci,
Giovanni Cazzaniga,
Andrea Biondi,
Suzanne Schnittger,
Torsten Haferlach,
Wolfgang Hiddemann,
Massimo F. Martelli,
Wei Gu,
Cristina Mecucci, and
Ildo Nicoletti
From the Institute of Hematology and Internal Medicine, University of Perugia, Italy; the Institute for Cancer Genetics and Department of Pathology, Columbia University, New York, NY; the Institute of Hematology, University of Bari, Italy; the Institute of Hematology, University of Foggia, Italy; the Institute of Hematology, University La Sapienza, Rome, Italy; the Pediatric Clinic, M. Tettamanti Research Center, San Gerardo Hospital, Monza, Italy; and the Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, Ludwig-Maximilian University, Munich, Germany.
We recently identified aberrant cytoplasmic expression of nucleophosmin (NPM) as the immunohistochemical marker of a large subgroup of acute myeloid leukemia (AML) (about one-third of adult AML) that is characterized by normal karyotype and mutations occurring at the exon-12 of the NPM gene. In this paper, we have elucidated the molecular mechanism underlying the abnormal cytoplasmic localization of NPM. All 29 AML-associated mutated NPM alleles so far identified encode abnormal proteins which have acquired at the C-terminus a nuclear export signal (NES) motif and lost both tryptophan residues 288 and 290 (or only the residue 290) which determine nucleolar localization. We show for the first time that both alterations are crucial for NPM mutant export from nucleus to cytoplasm. In fact, the cytoplasmic accumulation of NPM is blocked by leptomycin-B and ratjadones, specific exportin-1/Crm1-inhibitors, and by reinsertion of tryptophan residues 288 and 290, which respectively relocate NPM mutants in the nucleoplasm and nucleoli. NPM leukemic mutants in turn recruit the wild-type NPM from nucleoli to nucleoplasm and cytoplasm. These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus.
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