KRAS (G12D) cooperates with AML1/ETO to initiate a mouse model mimicking human acute myeloid leukemia.

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.

• 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)

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)

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