Nucleophosmin mutations in childhood acute myelogenous leukemia with normal karyotype

Abstract

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein involved in leukemia-associated chromosomal translocations, and it regulates the alternate reading frame (ARF)-p53 tumorsuppressor pathway. Recently, it has been demonstrated that mutations of the NPM1 gene alter the protein at its Cterminal, causing its cytoplasmic localization. Cytoplasmic NPM was detected in 35% of adult patients with primary non-French-American-British (FAB) classification M3 acute myeloid leukemia (AML), associated mainly with normal karyotype. We evaluated the prevalence of the NPM1 gene mutation in non-M3 childhood AML patients enrolled in the ongoing Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP-AML02) protocol in Italy. NPM1 mutations were found in 7 (6.5%) of 107 successfully analyzed patients. NPM1-mutated patients carried a normal karyotype (7/26, 27.1%) and were older in age. Thus, the NPM1 mutation is a frequent abnormality in AML patients without known genetic marker; the mutation may represent a new target to monitor minimal residual disease in AML and a potential candidate for alternative and targeted treatments. IntroductionChildhood acute myelogenous leukemia (AML) is a clinically and molecularly heterogeneous disease. 1,2 The identification of recurrent chromosomal abnormalities allows different prognostic subgroups to be defined. 1 Unfortunately, this is not yet feasible in a large proportion of cases (20%-25%) in which no chromosomal abnormalities are visible by conventional karyotyping and the underlying genetic lesion is still unknown.Progress has been recently made in the molecular characterization of adult AML with normal karyotype. Falini et al 3 reported that nucleophosmin 1 (NPM1), a nucleus-cytoplasm shuttling protein 4-7 involved in rearrangements in leukemias and lymphomas, [8][9][10] showed mutations at its C-terminal region, causing an aberrant cytoplasmic expression in the leukemic cells of about 35% of primary adult AML. NPM1 is a multifunctional protein that prevents protein aggregation in the nucleolus and regulates the assembly and transport of preribosomal particles through the nuclear membrane. 4 Since NPM1 is a multifunctional protein involved in the regulation of the ARF-p53 pathway, [11][12][13][14] it is likely that the mutation and/or ectopic location of the protein may play a leukemogenic role. 3,15 This finding prompted us to investigate the prevalence of NPM1 mutations in a large group of childhood AML patients and to correlate this finding with the major biologic and clinical features. Table 1. DNA from one NPM1-mutated patient at diagnosis was also investigated at remission. Informed consent has been obtained at each participating center. This study was approved by the AIEOP-AML Scientific Committee. Study design Patient samples Cytogenetic and molecular analysesCytogenetic investigations were performed by standard procedures. Reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis for promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha), a...

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…In addition, inactivation of nucleoplasmin could inhibit rRNA processing and disrupt the integrity of the nucleolus, ultimately leading to acute myeloid lymphoma (Cazzaniga et al, 2005).…”

Different types of NPM1 mutations in children and adults: evidence for an effect of patient age on the prevalence of the TCTG-tandem duplication in NPM1-exon 12

“…1 A pathologic activation of the RAS-RAF-MAP (mitogenactivated protein) kinase signal-transduction pathway from GM-CSF receptor to the nucleus is the key point of the pathophysiology of this disease. 3,4 In about 70% of JMML cases, this activation is due to mutations in RAS (25% of cases), NF1 (clinical diagnosis in about 11% of cases) or PTPN11 (35% of cases). [3][4][5] All these genetic aberrations have been demonstrated to be able to produce, in experimental models, the development of progressive myeloproliferative disorders.…”

“…3,4 In about 70% of JMML cases, this activation is due to mutations in RAS (25% of cases), NF1 (clinical diagnosis in about 11% of cases) or PTPN11 (35% of cases). [3][4][5] All these genetic aberrations have been demonstrated to be able to produce, in experimental models, the development of progressive myeloproliferative disorders. 4,6 However, even though one of these gene mutations can be observed in more than two-thirds of JMML patients, in the remaining affected children a specific genetic alteration has not been identified so far.…”

“…1 Few data exist on the incidence and relevance of NPM1-mutations in children. The study by Cazzaniga et al 4 is the only report specifically investigating NPM1-mutations in pediatric AML. They found a low overall prevalence of 6.5% (7/107 patients), and showed that cases with NPM1 mutation were older and frequently had a normal karyotype.…”

“…The most common mutation in this pediatric group was type B (6/9; 67%; Table 1). As Cazzaniga et al 4 also found only 1/7 cases with mutation A, we asked whether this distribution was by chance and compared the mutational spectrum of 434 recently analyzed adult patients with NPM1-mutations with the pediatric cases. The comparison of type A mutations (323/434 adults and 1/9 children) and non-type A mutations (111/434 adults and 8/9 children) showed a highly significant difference in the prevalence of this alteration (P ¼ 0.0002; Fisher's exact test).…”