4869

NPM1

B23|NPM;nucleophosmin (nucleolar phosphoprotein B23, numatrin);NPM1;nucleophosmin (nucleolar phosphoprotein B23, numatrin)

nucleolar protein NO38|nucleophosmin|nucleophosmin/nucleoplasmin family, member 1|numatrin

5q35.1

protein-coding

Partial deletion of the long arm of chromosome 5, del(5q), is the cytogenetic hallmark of the 5q-syndrome, a distinct subtype of myelodysplastic syndrome-refractory anemia (MDS-RA). Deletions of 5q also occur in the full spectrum of other de novo and therapy-related MDS and acute myeloid leukemia (AML) types, most often in association with other chromosome abnormalities. However, the loss of genetic material from 5q is believed to be of primary importance in the pathogenesis of ALL del(5q) disorders. In the present study, we performed fluorescence in situ hybridization (FISH) studies using a chromosome 5-specific whole chromosome painting probe and a 5q subtelomeric probe to determine the incidence of cryptic translocations. We studied archival fixed chromosome suspensions from 36 patients with myeloid disorders (predominantly MDS and AML) and del(5q) as the sole abnormality. In 3 AML patients studied, this identified a translocation of 5q subtelomeric sequences from the del(5q) to the short arm of an apparently normal chromosome 11. FISH with chromosome 11-specific subtelomeric probes confirmed the presence of 11p on the shortened 5q. Further FISH mapping confirmed that the 5q and 11p translocation breakpoints were the same in ALL 3 cases, between the nucleophosmin (NPM1) and fms-related tyrosine kinase 4 (FLT4) genes on 5q35 and the Harvey ras-1-related gene complex (HRC) and the radixin pseudogene (RDPX1) on 11p15.5. Importantly, ALL 3 patients with the cryptic t(5;11) were children: a total of 3 of 4 AML children studied. Two were classified as AML-M2 and the third was classified as M4. ALL 3 responded poorly to treatment and had short survival times, ranging from 10 to 18 months. Although del(5q) is rare in childhood AML, this study indicates that, within this subgroup, the incidence of cryptic t(5;11) may be high. It is significant that none of the 24 MDS patients studied, including 11 confirmed as having 5q-syndrome, had the translocation. Therefore, this appears to be a new nonrandom chromosomal translocation, specifically associated with childhood AML with a differentiated blast cell phenotype and the presence of a del(5q).

Nucleophosmin (NPM) is a nucleocytoplasmic shuttling protein involved in leukemia-associated chromosomal translocations, and it regulates the alternate reading frame (ARF)-p53 tumor-suppressor pathway. Recently, it has been demonstrated that mutations of the NPM1 gene alter the protein at its C-terminal, 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 Oncologiapediatrica (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.

BACKGROUND: miRNAs regulate gene expression, and thus play an important role in critical cellular processes. Aberrant miRNA expression patterns have been found in various types of cancer. So far, information about the expression of miRNAs in pediatric acute myeloid leukemia is limited. PROCEDURE: We studied expression ofmiR-29a, -155, -196a, and -196b by stem-loop based RT-qPCR in 82 pediatric acutemyeloid leukemia patients selected to represent relevant cytogenetic and molecular subgroups. RESULTS: High miR-196a and -b expression was observed in patients carrying MLL gene rearrangements (P < 0.001), NPM1 mutations (P < 0.001), or FLT3-ITD in a cytogenetically normal background (P ALL other patients. In contrast, CEBPA mutated cases had a low expression of miR-196a and -b (P expression of miR-196a and -b was correlated withexpression of neighboring HOXA and HOXB genes (Spearman's r = 0.46-0.82, P < 0.01). expression of miR-155 was not related to cytogenetic features but high expression of miR-155 was observed in FLT3-ITD (P = 0.001) and NPM1-mutated cases (P = 0.04). Lower miR-29a expression was mainly observed in MLL-rearranged pediatric acute myeloid leukemia, specifically in cases carrying t(10;11) (P < 0.001). CONCLUSIONS: We show aberrant expression of specific miRNAs in clinically relevant cytogenetic and molecular subgroups of pediatric acute myeloid leukemia, suggesting a role for these miRNAs in the underlying biology in these specific subgroups.#CI- Copyright (c) 2011 Wiley Periodicals, Inc.