U.K. researchers have used techniques for targeted gene disruption in mice to determine the processes by which mutations in the Npm1 gene can act to trigger the development of acute myeloid leukemia. The Welcome Trust Sanger Institute team’s findings demonstrated that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells caused Hox gene overexpression, enhanced self renewal, and expanded myelopoiesis. They hope the new insights into AML development at the cellular level will lead to the identification of potential new therapeutic targets. The research is published in Nature Genetics, in a paper titled, “Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice.”
The Sanger Institute team, led by consultant haematologist George Vassilou, M.D., generated a conditional knock-in mouse model of the most common form of Npm1c mutation, type A, and modified the Npm1 locus in mouse embryonic stem cells. They found that mutations in Npm1 gave normal blood cells the ability to renew themselves more efficiently and boosted production of myeloid cells. However, only three out of 10 mice developed leukemia, and in these animals the disease took a long time to manifest. This suggested the Npm1 mutation could kick-start the leukemic process, but wasn’t necessarily solely responsible for the disease developing, the authors note.
The researchers then used insertional mutagenesis techniques to generate mutations in other genes in the mice with altered Npm1 genes. Using this approach they found that Npm1 gene mutation works in concert with additional genes that are involved in cell proliferation and the control of genetic activity.
“In our mice two, or, in most cases, all three of these cellular processes were subverted,” notes senior author Allan Bradley. “In concert, these genetic mutations, which were concentrated on a tiny number of genes, transformed normal to leukemic cells. These findings give a much clearer view of how this difficult cancer develops and propagates.”
“Our approach to define the effects of a mutation in isolation and then map its collaborative oncogenic pathways provides a model for the study of other human cancer-associated mutations and can be used to complement and help decipher recent and impending whole cancer genome sequencing studies,” the authors conclude.