Abstract
Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.
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Acknowledgements
We thank Stanley Pounds for statistical analyses and Zhongling Cai for technical assistance. This work was supported in part by National Cancer Institute grants P01 CA71907-10 (JRD), CA-21765 (Cancer Center CORE grant to St Jude Children's Research Hospital) by the American Lebanese and Syrian Associated Charities of St Jude Children's Research Hospital. CGM is supported by a St Jude Children's Research Hospital Physician Scientist Fellowship, a National Health and Medical Research Council (Australia) CJ Martin Fellowship, a Haematology Society of Australia and New Zealand/AMGEN Traveling Fellowship and a Royal College of Physicians of Australasia/CSL Fellowship.
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Mullighan, C., Kennedy, A., Zhou, X. et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia 21, 2000–2009 (2007). https://doi.org/10.1038/sj.leu.2404808
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DOI: https://doi.org/10.1038/sj.leu.2404808
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