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


CONCLUSIONS
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.
Laboratory Animal Center of Second Military Medical University Shanghai, Shanghai, China.
Shanmin
S
Zhao
Yuxia
Y
Zhang
Kun
K
Sha
Qiu
Q
Tang
Xiaohua
X
Yang
Chenlin
C
Yu
Zhixue
Z
Liu
Wei
W
Sun
Liping
L
Cai
Chen
C
Xu
Shufang
S
Cui
D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D009857:Oncogenes; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000075142:RUNX1 Translocation Partner 1 Protein; D012190:Retroviridae / Q000378:metabolism; D014161:Transduction, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D016283:Proto-Oncogene Proteins p21(ras)