https://scholars.lib.ntu.edu.tw/handle/123456789/504020
標題: | A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment | 作者: | Chou S.-H. BOR-SHENG KO Chiou J.-S. Hsu Y.-C. MONG-HSUN TSAI Chiu Y.-C. Yu I.-S. SHU-WHA LIN HSIN-AN HOU Kuo Y.-Y. Lin H.-M. Wu M.-F. WEN-CHIEN CHOU HWEI-FANG TIEN |
公開日期: | 2012 | 卷: | 7 | 期: | 11 | 起(迄)頁: | e49769 | 來源出版物: | PLoS ONE | 摘要: | 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 (Npm1c+/c+) mice showed embryonic lethality before day E8.5, wheras heterozygous (Npm1wt/c+) mice appeared healthy at birth and were fertile. Approximately 36% of Npm1wt/c+ mice developed myeloproliferative disease (MPD) with extramedullary hematopoiesis. Those Npm1wt/c+ mice that did not develop MPD nevertheless gradually developed monocytosis and showed increased numbers of marrow myeloid precursors. This second group of Npm1wt/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. ? 2012 Chou et al. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/504020 | ISSN: | 1932-6203 | DOI: | 10.1371/journal.pone.0049769 | SDG/關鍵字: | chemokine receptor CXCR4; nucleophosmin; stromal cell derived factor 1; animal cell; animal experiment; animal model; animal tissue; article; cell count; controlled study; extramedullary hematopoiesis; gene expression; gene mutation; human; human cell; knockout mouse; major clinical study; microarray analysis; monocytosis; mouse; myeloid progenitor cell; myeloproliferative disorder; nonhuman; nucleophosmin gene; stem cell expansion; Animals; Cell Proliferation; Chemokine CXCL12; Disease Models, Animal; Founder Effect; Gene Expression; Gene Expression Profiling; Gene Knock-In Techniques; Heterozygote; Humans; Leukemia, Myeloid, Acute; Mice; Mice, Transgenic; Mutation; Myeloid Cells; Myelopoiesis; Nuclear Proteins; Oligonucleotide Array Sequence Analysis; Receptors, CXCR4; Mus |
顯示於: | 醫學檢驗暨生物技術學系 |
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