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A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment

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) t...

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Autores principales: Chou, Shiu-Huey, Ko, Bor-Sheng, Chiou, Ji-Shain, Hsu, Yueh-Chwen, Tsai, Mong-Hsun, Chiu, Yu-Chiao, Yu, I-Shing, Lin, Shu-Wha, Hou, Hsin-An, Kuo, Yi-Yi, Lin, Hsiu-Mei, Wu, Ming-Fang, Chou, Wen-Chien, Tien, Hwei-Fang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511491/
https://www.ncbi.nlm.nih.gov/pubmed/23226219
http://dx.doi.org/10.1371/journal.pone.0049769
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author Chou, Shiu-Huey
Ko, Bor-Sheng
Chiou, Ji-Shain
Hsu, Yueh-Chwen
Tsai, Mong-Hsun
Chiu, Yu-Chiao
Yu, I-Shing
Lin, Shu-Wha
Hou, Hsin-An
Kuo, Yi-Yi
Lin, Hsiu-Mei
Wu, Ming-Fang
Chou, Wen-Chien
Tien, Hwei-Fang
author_facet Chou, Shiu-Huey
Ko, Bor-Sheng
Chiou, Ji-Shain
Hsu, Yueh-Chwen
Tsai, Mong-Hsun
Chiu, Yu-Chiao
Yu, I-Shing
Lin, Shu-Wha
Hou, Hsin-An
Kuo, Yi-Yi
Lin, Hsiu-Mei
Wu, Ming-Fang
Chou, Wen-Chien
Tien, Hwei-Fang
author_sort Chou, Shiu-Huey
collection PubMed
description 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.
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spelling pubmed-35114912012-12-05 A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment Chou, Shiu-Huey Ko, Bor-Sheng Chiou, Ji-Shain Hsu, Yueh-Chwen Tsai, Mong-Hsun Chiu, Yu-Chiao Yu, I-Shing Lin, Shu-Wha Hou, Hsin-An Kuo, Yi-Yi Lin, Hsiu-Mei Wu, Ming-Fang Chou, Wen-Chien Tien, Hwei-Fang PLoS One Research Article 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. Public Library of Science 2012-11-30 /pmc/articles/PMC3511491/ /pubmed/23226219 http://dx.doi.org/10.1371/journal.pone.0049769 Text en © 2012 Chou et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Chou, Shiu-Huey
Ko, Bor-Sheng
Chiou, Ji-Shain
Hsu, Yueh-Chwen
Tsai, Mong-Hsun
Chiu, Yu-Chiao
Yu, I-Shing
Lin, Shu-Wha
Hou, Hsin-An
Kuo, Yi-Yi
Lin, Hsiu-Mei
Wu, Ming-Fang
Chou, Wen-Chien
Tien, Hwei-Fang
A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title_full A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title_fullStr A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title_full_unstemmed A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title_short A Knock-In Npm1 Mutation in Mice Results in Myeloproliferation and Implies a Perturbation in Hematopoietic Microenvironment
title_sort knock-in npm1 mutation in mice results in myeloproliferation and implies a perturbation in hematopoietic microenvironment
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511491/
https://www.ncbi.nlm.nih.gov/pubmed/23226219
http://dx.doi.org/10.1371/journal.pone.0049769
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