title: A knock-in Npm1 mutation in mice results in myeloproliferation and implies a perturbation in hematopoietic microenvironment.
abstract: Somatic Nucleophosmin (NPM1) mutation frequently occurs in acute myeloid leukemia (AML), but its role in leukemogenesis remains unclear. This study reports the first "conventional" knock-in mouse model of Npm1 mutation, which was achieved by inserting TCTG after nucleotide c.857 (c.854_857dupTCTG) to mimic human mutation without any "humanized" sequence. The resultant mutant peptide differed slightly different from that in humans but exhibited cytoplasmic pulling force. Homozygous (Npm1(c+/c+)) mice showed embryonic lethality before day E8.5, wheras heterozygous (Npm1(wt/c+)) mice appeared healthy at birth and were fertile. Approximately 36% of Npm1(wt/c+) mice developed myeloproliferative disease (MPD) with extramedullary hematopoiesis. Those Npm1(wt/c+) mice that did not develop MPD nevertheless gradually developed monocytosis and showed increased numbers of marrow myeloid precursors. This second group of Npm1(wt/c+) mice also showed compromised cobblestone area formation, suggesting pathology in the hematopoietic niche. Microarray experiments and bioinformatic analysis on mice myeloid precursor cells and 227 human samples revealed the expression of CXCR4/CXCL12-related genes was significantly suppressed in mutant cells from both mice and humans. Thus, our mouse model demonstrated that Npm1 mutation can result in MPD, but is insufficient for leukemogenesis. Perturbation of hematopoietic niche in mutant hematopoietic stem cells (implied by underrepresentation of CXCR4/CXCL12-related genes) may be important in the pathogenesis of NPM1 mutations.
authors.affiliation: Department of Life Science, Fu-Jen University, Taipei, Taiwan.
authors.forename: Shiu-Huey
authors.initials: SH
authors.lastname: Chou
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.forename: Ji-Shain
authors.initials: JS
authors.lastname: Chiou
authors.forename: Yueh-Chwen
authors.initials: YC
authors.lastname: Hsu
authors.forename: Mong-Hsun
authors.initials: MH
authors.lastname: Tsai
authors.forename: Yu-Chiao
authors.initials: YC
authors.lastname: Chiu
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Hou
authors.forename: Yi-Yi
authors.initials: YY
authors.lastname: Kuo
authors.forename: Hsiu-Mei
authors.initials: HM
authors.lastname: Lin
authors.forename: Ming-Fang
authors.initials: MF
authors.lastname: Wu
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Chou
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tien
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018703:Founder Effect; D015870:Gene Expression; D020869:Gene Expression Profiling; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D038042:Myelopoiesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D020411:Oligonucleotide Array Sequence Analysis; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D019718:Receptors, CXCR4; D000090243:Nucleophosmin