A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)

Genes

Maria Grazia Mameli¹  Enrico Tiacci²  Brunangelo Falini²  Maria Paola Martelli²  Alessandra Venanzi²  Roberta Rossi²  Paolo Sportoletti²  Giuseppe Avvisati³  Ombretta Annibali³  Giovanni Martino⁴ 

[1] Hematology Section, “Santa Maria della Misericordia” Hospital of Perugia, 06132 Perugia, Italy;Hematology and Clinical Immunology, Centro di Ricerche Emato-Oncologiche (CREO), University of Perugia, 06132 Perugia, Italy;Hematology and Stem Cell Transplant Unit, Campus Bio-Medico University of Rome, 00128 Rome, Italy;Pathology Unit, Azienda Ospedaliera Santa Maria di Terni, University of Perugia, 05100 Terni, Italy;

关键词: acute myeloid leukemia;    nucleophosmin;    NPM1;    nuclear export signal (NES);    exportin-1/XPO1;   

DOI  :  10.3390/genes12091426

来源: DOAJ

【 摘 要 】

Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis.

【 授权许可】

Unknown