Abstract | BACKGROUND/AIMS: It has been demonstrated that KRAS mutations represent about 90% of cancer-associated mutations, and that KRAS mutations play an essential role in neoplastic transformation. Cancer-associated RAS mutations occur frequently in acute myeloid leukemia (AML), suggesting a functional role for Ras in leukemogenesis. METHODS: We successfully established a mouse model of human leukemia by transplanting bone marrow cells co-transfected with the K-ras (G12D) mutation and AML1/ETO fusion protein. RESULTS: Mice transplanted with AML/ETO+KRAS co-transduced cells had the highest mortality rate than mice transplanted with AML/ETO- or KRAS-transduced cells (115d vs. 150d). Upon reaching a terminal disease stage, EGFP-positive cells dominated their spleen, lymph nodes, peripheral blood and central nervous system tissue. Immunophenotyping, cytologic analyses revealed that AML/ETO+KRAS leukemias predominantly contained immature myeloid precursors (EGFP(+)/c-Kit(+)/Mac-1(-)/Gr-1(-)). Histologic analyses revealed that massive leukemic infiltrations were closely packed in dense sheets that effaced the normal architecture of spleen and thymus in mice transplanted with AML1/ETO + KRAS co-transduced cells. K-ras mRNA and protein expression were upregulated in bone marrow cells of the K-ras group and AML1/ETO + Kras group. The phosphorylation of MEK/ERK was significantly enhanced in the AML1/ETO + Kras group. The similar results of the AML1/ETO + Nras group were consistent with those reported previously. CONCLUSION: Co-transduction of Kras(G12D) and AML1/ETO induces acute monoblastic leukemia. Since expression of mutant K-ras alone was insufficient to induce leukemia, this model may be useful for investigating the multi-step leukemogenesis model of human leukemia.
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Authors | Shanmin Zhao, Yuxia Zhang, Kun Sha, Qiu Tang, Xiaohua Yang, Chenlin Yu, Zhixue Liu, Wei Sun, Liping Cai, Chen Xu, Shufang Cui |
Journal | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
(Cell Physiol Biochem)
Vol. 33
Issue 1
Pg. 78-87
( 2014)
ISSN: 1421-9778 [Electronic] Germany |
PMID | 24480914
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- AML1-ETO fusion protein, human
- Core Binding Factor Alpha 2 Subunit
- KRAS protein, human
- Oncogene Proteins, Fusion
- RUNX1 Translocation Partner 1 Protein
- Proto-Oncogene Proteins p21(ras)
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Topics |
- Animals
- Core Binding Factor Alpha 2 Subunit
(metabolism)
- Disease Models, Animal
- Genetic Vectors
(metabolism)
- Humans
- Leukemia, Myeloid, Acute
(pathology)
- Male
- Mice, Inbred C57BL
- Mutation
(genetics)
- Oncogene Proteins, Fusion
(metabolism)
- Oncogenes
- Proto-Oncogene Proteins p21(ras)
(genetics)
- RUNX1 Translocation Partner 1 Protein
- Retroviridae
(metabolism)
- Transduction, Genetic
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