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Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.

ABSTRACT: Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML.

SUBMITTER: Vassiliou GS

PROVIDER: S-EPMC3084174 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.

Vassiliou George S GS Cooper Jonathan L JL Rad Roland R Li Juan J Rice Stephen S Uren Anthony A Rad Lena L Ellis Peter P Andrews Rob R Banerjee Ruby R Grove Carolyn C Wang Wei W Liu Pentao P Wright Penny P Arends Mark M Bradley Allan A

Nature genetics 20110327 5

Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene ov ...[more]

PMID: 21441929

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Dataset Information

Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.

Publications

Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.

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