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Citations to this article

Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease
Iris T. Chan, … , Tyler Jacks, D. Gary Gilliland
Iris T. Chan, … , Tyler Jacks, D. Gary Gilliland
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):528-538. https://doi.org/10.1172/JCI20476.
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Article Oncology Article has an altmetric score of 1

Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease

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Abstract

Oncogenic ras alleles are among the most common mutations found in patients with acute myeloid leukemia (AML). Previously, the role of oncogenic ras in cancer was assessed in model systems overexpressing oncogenic ras from heterologous promoters. However, there is increasing evidence that subtle differences in gene dosage and regulation of gene expression from endogenous promoters play critical roles in cancer pathogenesis. We characterized the role of oncogenic K-ras expressed from its endogenous promoter in the hematopoietic system using a conditional allele and IFN-inducible, Cre-mediated recombination. Mice developed a completely penetrant myeloproliferative syndrome characterized by leukocytosis with normal maturation of myeloid lineage cells; myeloid hyperplasia in bone marrow; and extramedullary hematopoiesis in the spleen and liver. Flow cytometry confirmed the myeloproliferative phenotype. Genotypic and Western blot analysis demonstrated Cre-mediated excision and expression, respectively, of the oncogenic K-ras allele. Bone marrow cells formed growth factor–independent colonies in methylcellulose cultures, but the myeloproliferative disease was not transplantable into secondary recipients. Thus, oncogenic K-ras induces a myeloproliferative disorder but not AML, indicating that additional mutations are required for AML development. This model system will be useful for assessing the contribution of cooperating mutations in AML and testing ras inhibitors in vivo.

Authors

Iris T. Chan, Jeffery L. Kutok, Ifor R. Williams, Sarah Cohen, Lauren Kelly, Hirokazu Shigematsu, Leisa Johnson, Koichi Akashi, David A. Tuveson, Tyler Jacks, D. Gary Gilliland

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Total citations by year

Year: 2025 2024 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 2005 Total
Citations: 1 4 3 7 2 6 5 5 6 5 12 7 4 11 13 12 8 11 10 4 136
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Citations to this article in year 2008 (8)

Title and authors Publication Year
Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease
AM Wahlstrom, BA Cutts, M Liu, A Lindskog, C Karlsson, AK Sjogren, KM Andersson, SG Young, MO Bergo
Blood 2008
K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors
T Kindler, MG Cornejo, C Scholl, J Liu, DS Leeman, JE Haydu, S Fröhling, BH Lee, DG Gilliland
Blood 2008
Effect of Ras inhibition in hematopoiesis and BCR/ABL leukemogenesis
KJ Baum, R Ren
Journal of Hematology & Oncology 2008
Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model
L Li, O Piloto, HB Nguyen, K Greenberg, K Takamiya, F Racke, D Huso, D Small
Blood 2008
Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia
S Archambeault, NJ Flores, A Yoshimi, CP Kratz, M Reising, A Fischer, P Noellke, F Locatelli, P Sedlacek, C Flotho, M Zecca, PD Emanuel, RP Castleberry, CM Niemeyer, P Bader, ML Loh
Blood 2008
Single-Cell Profiling Identifies Aberrant STAT5 Activation in Myeloid Malignancies with Specific Clinical and Biologic Correlates
N Kotecha, NJ Flores, JM Irish, EF Simonds, DS Sakai, S Archambeault, E Diaz-Flores, M Coram, KM Shannon, GP Nolan, ML Loh
Cancer Cell 2008
Genome profiling of chronic myelomonocytic leukemia: frequent alterations of RAS and RUNX1genes
V Gelsi-Boyer, V Trouplin, J Adélaïde, N Aceto, V Remy, S Pinson, C Houdayer, C Arnoulet, D Sainty, M Bentires-Alj, S Olschwang, N Vey, MJ Mozziconacci, D Birnbaum, M Chaffanet
BMC Cancer 2008
Genetically modified mouse models in cancer studies.
Santos J, Fernández-Navarro P, Villa-Morales M, González-Sánchez L, Fernández-Piqueras J
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 2008

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