KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia
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 rol...
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| Format: | Article |
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Cell Physiol Biochem Press GmbH & Co KG
2014-01-01
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| Series: | Cellular Physiology and Biochemistry |
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| Online Access: | http://www.karger.com/Article/FullText/356651 |
| _version_ | 1819170407344766976 |
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| author | Shanmin Zhao Yuxia Zhang Kun Sha Qiu Tang Xiaohua Yang Chenlin Yu Zhixue Liu Wei Sun Liping Cai Chen Xu Shufang Cui |
| author_facet | Shanmin Zhao Yuxia Zhang Kun Sha Qiu Tang Xiaohua Yang Chenlin Yu Zhixue Liu Wei Sun Liping Cai Chen Xu Shufang Cui |
| author_sort | Shanmin Zhao |
| collection | DOAJ |
| description | 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 KrasG12D 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. |
| first_indexed | 2024-12-22T19:34:54Z |
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| institution | Directory Open Access Journal |
| issn | 1015-8987 1421-9778 |
| language | English |
| last_indexed | 2024-12-22T19:34:54Z |
| publishDate | 2014-01-01 |
| publisher | Cell Physiol Biochem Press GmbH & Co KG |
| record_format | Article |
| series | Cellular Physiology and Biochemistry |
| spelling | doaj.art-02c472c4062f4d0da9eef64d1ca2d9142022-12-21T18:15:00ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782014-01-01331788710.1159/000356651356651KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid LeukemiaShanmin ZhaoYuxia ZhangKun ShaQiu TangXiaohua YangChenlin YuZhixue LiuWei SunLiping CaiChen XuShufang CuiBackground/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 KrasG12D 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.http://www.karger.com/Article/FullText/356651Ras mutationsAcute myeloid leukemiaLeukemogenesisK-rasAML1/ETO |
| spellingShingle | Shanmin Zhao Yuxia Zhang Kun Sha Qiu Tang Xiaohua Yang Chenlin Yu Zhixue Liu Wei Sun Liping Cai Chen Xu Shufang Cui KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia Cellular Physiology and Biochemistry Ras mutations Acute myeloid leukemia Leukemogenesis K-ras AML1/ETO |
| title | KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia |
| title_full | KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia |
| title_fullStr | KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia |
| title_full_unstemmed | KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia |
| title_short | KRAS (G12D) Cooperates with AML1/ETO to Initiate a Mouse Model Mimicking Human Acute Myeloid Leukemia |
| title_sort | kras g12d cooperates with aml1 eto to initiate a mouse model mimicking human acute myeloid leukemia |
| topic | Ras mutations Acute myeloid leukemia Leukemogenesis K-ras AML1/ETO |
| url | http://www.karger.com/Article/FullText/356651 |
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