Recent studies have identified mutations in the nucleophosmin (NPM) gene in up to one-third of cases of acute myeloid leukemia (AML) lacking a recurring cytogenetic abnormality. NPM mutations (NPMm+) result in aberrant cytoplasmic localization of nucleophosmin, which may potentially perturb multiple cellular pathways including cell cycle regulation. However the exact mechanisms by which mutant NPM contributes to leukemogenesis are unclear. Gene expression analysis may identify mediators or pathways in NPMm+ AML that are important in the development of leukemia. We have examined NPM mutation status in a 93 cases of pediatric AML and correlated mutation status with gene expression profile. All major AML subgroups were studied including AML-ETO (n=18), MLL rearranged (n=14) CBFB-MYH11 (n=13), PML-RARA and variants (n=4), acute megakaryoblastic leukemia (n=4), and AML with normal cytogenetics (n=20), or non-recurring cytogenetic abnormalities (n=20). Exon 12 of NPM was PCR amplified, sequenced, and abnormal cases verified by cloning and sequencing. Gene expression profiling was performed using Affymetrix U133A arrays. Six cases with tetranucleotide insertion mutations in NPM exon 12 were identified. Four had normal cytogenetics, and two non-recurring cytogenetic abnormalities. Differential gene expression between NPMm+ and NPMm- AML (either all NPMm- cases, or only those NPMm- cases lacking recurring cytogenetic abnormalities) was assessed by t-test. NPMm+ AML was characterized by upregulation of multiple homeobox genes (e.g. HOXA9, A10, B2, B6) as well as multiple genes with known or potential roles in tumorigenesis, such as MEIS1 and the NPM fusion partner ALK. This pattern of disordered HOX expression is similar to that of MLL-rearranged leukemia; however comparison of the signatures of NPMm+ and MLL-rearranged leukemia identified important differences, such as upregulation of HOXB2, B3, B6 and D4 in NPMm+ AML but not MLL-leukemia. These results confirm a recently published report describing perturbed HOX expression in NPMm+ AML (

Alcalay et al. Blood 2005;106:899
), and provide the first evidence that the NPMm+ signature is similar to but distinct from MLL-rearranged AML. These findings provide important insights into the pathogenesis of NPMm+ leukemia, and support the hypothesis that mutated NPM dysregulates HOX expression via a different mechanism than MLL rearrangement.

Topics:
genes, homeobox, leukemia, leukemia, myelocytic, acute, molecular profiling, mutation, npm1 gene, genes, vif, pediatrics, gene expression profiling, acute megakaryocytic leukemias

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2005, The American Society of Hematology
2005
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