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Rapid Detection of Nucleophosmin (NPM1) Mutations in Acute Myeloid Leukemia by Denaturing HPLC

¹ Dipartimento di Biopatologia e Diagnostica per Immagini and ³ Dipartimento di Medicina Interna, University Tor Vergata, Rome, Italy; ² Laboratorio di Ricerca IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy; ⁴ Dipartimento di Medicina di Laboratorio, Policlinico Tor Vergata, Rome, Italy;

^aaddress correspondence to this author at: Dipartimento di Biopatologia e Diagnostica per Immagini, Università Tor Vergata, via Montpellier, 1-00133 Rome, Italy; fax 39-0672596281, e-mail francesco.lo.coco@uniroma2.it

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Nucleophosmin (NPM1) is a multifunctional, highly conserved protein found most frequently in nucleoli. NPM1 acts as a molecular chaperone (1) and is thought to participate in preribosome maturation and centrosome duplication(2); in addition, it has been implicated in the regulation of the ArF-p53 tumor suppressor pathway(3)(4).

NPM1 mutations have recently been reported to occur at high frequency in acute myeloid leukemia (AML), for which they currently represent the most common detectable genetic lesion (35% of cases). This abnormality is strongly associated with normal-karyotype AML and has never been detected in AMLs bearing major cytogenetic abnormalities. It has not been observed in other hematopoietic tumors (5). Two main types of mutations have been described to date. The first and most frequent consists of a 4-nucleotide (nt) insertion (YWTG; YUPAC code) downstream from nucleotide 959; the second is deletion of a GGAGG sequence at positions 965 through 969 and substitution with 9 extra nt (GenBank accession no. NM_002520). Both mutations lead to aberrant cytoplasmic localization of NPM1 as shown after immunostaining with anti-NPM1 monoclonal antibodies. In addition to their high frequency and clustering with normal karyotype, NPM1 mutations may identify a subset of AMLs with distinct response to therapy(5). Together, these findings may have repercussions in AML classification and suggest that analysis of NPM1 mutational status should integrate modern genetic characterization of AML. We . . . [Full Text of this Article]

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