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A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia.

Saland E, Boutzen H, Castellano R, Pouyet L, Griessinger E, Larrue C, de Toni F, Scotland S, David M, Danet-Desnoyers G, Vergez F, Barreira Y, Collette Y, Récher C, Sarry JE - Blood Cancer J (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Research Center of Toulouse, INSERM, U1037, Toulouse, France [2] University of Toulouse, Toulouse, France.

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 IL2Rγc() 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.

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Related in: MedlinePlus

Analysis of the expression of major myeloid cell surface markers in AML cell lines before and after xenotransplantation. The immunophenotype of HL-60, MV4-11, U937 and KG1a cells was analyzed on BD LSRII Fortessa Flow Cytometer using human CD45, CD44, CD33, CD34, CD38, CD45RA and CD123 before and after xenotransplantation in our NSG mice model. All AML cell lines are SSClow, CD45, CD44 and CD33 positive in vitro and in vivo.
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fig4: Analysis of the expression of major myeloid cell surface markers in AML cell lines before and after xenotransplantation. The immunophenotype of HL-60, MV4-11, U937 and KG1a cells was analyzed on BD LSRII Fortessa Flow Cytometer using human CD45, CD44, CD33, CD34, CD38, CD45RA and CD123 before and after xenotransplantation in our NSG mice model. All AML cell lines are SSClow, CD45, CD44 and CD33 positive in vitro and in vivo.

Mentions: We next addressed whether the immunophenotype of AML cell lines was conserved in vivo. The expression level of various myeloid cell surface markers such as CD45, CD33, CD44, CD34, CD38, CD45RA and CD123 was analyzed for four AML cell lines before and after xenotransplantation (Figure 4). Most of those markers appeared globally unchanged during engraftment, however, we found that the transplantation of HL-60 cells in mice also led to the appearance of a second population CD44dim (Figure 4, second column). Moreover, the frequency of CD34+CD38+ was significantly increased in vivo to the detriment of the CD34+CD38- population (Figure 4, third column). With the sole exception of the CD38 marker, the NSG-based model of AML maintains cell phenotype more consistently than in the NOD-SCID model.12


A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia.

Saland E, Boutzen H, Castellano R, Pouyet L, Griessinger E, Larrue C, de Toni F, Scotland S, David M, Danet-Desnoyers G, Vergez F, Barreira Y, Collette Y, Récher C, Sarry JE - Blood Cancer J (2015)

Analysis of the expression of major myeloid cell surface markers in AML cell lines before and after xenotransplantation. The immunophenotype of HL-60, MV4-11, U937 and KG1a cells was analyzed on BD LSRII Fortessa Flow Cytometer using human CD45, CD44, CD33, CD34, CD38, CD45RA and CD123 before and after xenotransplantation in our NSG mice model. All AML cell lines are SSClow, CD45, CD44 and CD33 positive in vitro and in vivo.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4382660&req=5

fig4: Analysis of the expression of major myeloid cell surface markers in AML cell lines before and after xenotransplantation. The immunophenotype of HL-60, MV4-11, U937 and KG1a cells was analyzed on BD LSRII Fortessa Flow Cytometer using human CD45, CD44, CD33, CD34, CD38, CD45RA and CD123 before and after xenotransplantation in our NSG mice model. All AML cell lines are SSClow, CD45, CD44 and CD33 positive in vitro and in vivo.
Mentions: We next addressed whether the immunophenotype of AML cell lines was conserved in vivo. The expression level of various myeloid cell surface markers such as CD45, CD33, CD44, CD34, CD38, CD45RA and CD123 was analyzed for four AML cell lines before and after xenotransplantation (Figure 4). Most of those markers appeared globally unchanged during engraftment, however, we found that the transplantation of HL-60 cells in mice also led to the appearance of a second population CD44dim (Figure 4, second column). Moreover, the frequency of CD34+CD38+ was significantly increased in vivo to the detriment of the CD34+CD38- population (Figure 4, third column). With the sole exception of the CD38 marker, the NSG-based model of AML maintains cell phenotype more consistently than in the NOD-SCID model.12

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Research Center of Toulouse, INSERM, U1037, Toulouse, France [2] University of Toulouse, Toulouse, France.

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 IL2Rγc() 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.

Show MeSH
Related in: MedlinePlus