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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
Citation information
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Citations to this article in year 2011 (11)

Title and authors Publication Year
PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice
John Welch, Wenlin Yuan, Tim Ley
Journal of Clinical Investigation 2011
The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine
EI Ahmad, HH Gawish, NM Azizi, AM Elhefni
OncoTargets and therapy 2011
A MEK Inhibitor Abrogates Myeloproliferative Disease in Kras Mutant Mice
N Lyubynska, MF Gorman, JO Lauchle, WX Hong, JK Akutagawa, K Shannon, BS Braun
Science Translational Medicine 2011
RAS oncogenes: weaving a tumorigenic web
Y Pylayeva-Gupta, E Grabocka, D Bar-Sagi
Nature Reviews Cancer 2011
Critical requirement for Stat5 in a mouse model of polycythemia vera
D Yan, RE Hutchison, G Mohi
Blood 2011
Prognostic Significance of NRAS Gene Mutations in Children with Acute Myelogenous Leukemia
RM Aly, MR El-Sharnoby, AA Hagag
Mediterranean journal of hematology and infectious diseases 2011
Constitutive MAP Kinase Activation in Hematopoietic Stem Cells Induces a Myeloproliferative Disorder
E Chung, CL Hsu, M Kondo
PloS one 2011
Distinct requirements of hematopoietic stem cell activity and Nras G12D signaling in different cell types during leukemogenesis
J Wang, Y Liu, LX Tan, JC Lo, J Du, MJ Ryu, EA Ranheim, J Zhang
Cell cycle (Georgetown, Tex.) 2011
Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner
J Wang, Y Liu, Z Li, Z Wang, LX Tan, MJ Ryu, B Meline, J Du, KH Young, E Ranheim, Q Chang, J Zhang
Blood 2011
Acute sensitivity of the oral mucosa to oncogenic K-ras
L der Weyden, MP Alcolea, PH Jones, AG Rust, MJ Arends, DJ Adams
The Journal of Pathology 2011
KRASG12V Enhances Proliferation and Initiates Myelomonocytic Differentiation in Human Stem/Progenitor Cells via Intrinsic and Extrinsic Pathways
S Fatrai, D van Gosliga, L Han, SM Daenen, E Vellenga, JJ Schuringa
The Journal of biological chemistry 2011

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