title: 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.
authors: Mouse Genomics Team, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. gsv20@sanger.ac.uk
authors: George S
authors: GS
authors: Vassiliou
authors: Jonathan L
authors: JL
authors: Cooper
authors: Roland
authors: R
authors: Rad
authors: Juan
authors: J
authors: Li
authors: Stephen
authors: S
authors: Rice
authors: Anthony
authors: A
authors: Uren
authors: Lena
authors: L
authors: Rad
authors: Peter
authors: P
authors: Ellis
authors: Rob
authors: R
authors: Andrews
authors: Ruby
authors: R
authors: Banerjee
authors: Carolyn
authors: C
authors: Grove
authors: Wei
authors: W
authors: Wang
authors: Pentao
authors: P
authors: Liu
authors: Penny
authors: P
authors: Wright
authors: Mark
authors: M
authors: Arends
authors: Allan
authors: A
authors: Bradley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018450:Disease Progression; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D038042:Myelopoiesis / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011994:Recombinant Proteins / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D018398:Homeodomain Proteins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D000090243:Nucleophosmin