Abstract
Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγcnull mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies.
Highlights
Acute myeloid leukemia (AML) is the most common adult acute leukemia and is characterized by clonal expansion of immature myeloblasts, initiating from rare leukemic stem or progenitor cells
The advantages of using well-established AML cell lines as compared with primary patient samples are the unlimited access to a large amount of human AML cells and a faster engraftment in immunodeficient mice
We analyzed in vivo the five most commonly used AML cell lines with a range of molecular abnormalities, clinical, biological and immunophenotypical characteristics (Table 1)
Summary
Acute myeloid leukemia (AML) is the most common adult acute leukemia and is characterized by clonal expansion of immature myeloblasts, initiating from rare leukemic stem or progenitor cells. In Europe and the USA, the incidence and mortality rates of AML are about 5 to 8/100.000 and 4 to 6/100.000 per year, respectively.[1] Despite a high rate of complete remission after treatment with genotoxic agents, the relapse rate remains very high and the prognosis very poor. Front-line chemotherapy is highly effective in ablating leukemic cells, but distant relapses are observed in the majority of patients, characterized by a refractory phase during which no other treatment has shown any efficacy far. Relapses are caused by malignant cell regrowth initiated by chemoresistant leukemic clones.[2,3]
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