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Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation.

Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D, Gerondakis S, Nutt SL, Green DR, Strasser A - J. Cell Biol. (2004)

Bottom Line: Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors.Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas.Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.

ABSTRACT
Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors. To investigate their in vivo role in lymphomagenesis, an IgH enhancer-driven c-myc transgene was crossed onto Apaf-1(-/-) and caspase-9(-/-) mice. Due to perinatal lethality, Emu-myc transgenic Apaf-1(-/-) or caspase-9(-/-) fetal liver cells were used to reconstitute lethally irradiated recipient mice. Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas. Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

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Hematologic parameters of preneoplastic mice. (A) Bone marrow cellularity (per 2 femurs) and B cell and pre–B cell counts. (B) Spleen cellularity. Data represent the arithmetic means ± SD from four to eight mice of each genotype.
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fig5: Hematologic parameters of preneoplastic mice. (A) Bone marrow cellularity (per 2 femurs) and B cell and pre–B cell counts. (B) Spleen cellularity. Data represent the arithmetic means ± SD from four to eight mice of each genotype.

Mentions: We also examined whether loss of Apaf-1 had an effect on the preneoplastic B cell phenotype induced by Eμ-myc transgene expression. This was done by measuring total leukocyte numbers and numbers of B lymphocytes in blood, bone marrow, spleen, and lymph nodes in mice reconstituted with Eμ-myc/Apaf-1+/+ or Eμ-myc/Apaf-1−/− fetal liver cells 12 wk after transplantation (range = 5–27, and median and mean = 12 wk), an earlier time than most reconstituted mice succumbed to lymphoma (range = 5–77, median = 27, and mean = 31 wk). Absence of significant numbers of tumor cells in all mice used for these analyses was proven by showing that transplanting 106 spleen cells into nonirradiated histocompatible mice did not cause lymphoma (unpublished data). No differences in pre–B cell (B220+sIgM−) or B cell (B220+sIgM+) numbers were found between mice reconstituted with Eμ-myc/Apaf-1+/+ or Eμ-myc/Apaf-1−/− stem cells (Fig. 5). As previously reported (Langdon et al., 1986), Eμ-myc expression caused a reduction in numbers of mature B cells in bone marrow compared with wild-type mice; this is thought to be a consequence of the proapoptotic and differentiation inhibiting effects of myc in B lymphocytes.


Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation.

Scott CL, Schuler M, Marsden VS, Egle A, Pellegrini M, Nesic D, Gerondakis S, Nutt SL, Green DR, Strasser A - J. Cell Biol. (2004)

Hematologic parameters of preneoplastic mice. (A) Bone marrow cellularity (per 2 femurs) and B cell and pre–B cell counts. (B) Spleen cellularity. Data represent the arithmetic means ± SD from four to eight mice of each genotype.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171953&req=5

fig5: Hematologic parameters of preneoplastic mice. (A) Bone marrow cellularity (per 2 femurs) and B cell and pre–B cell counts. (B) Spleen cellularity. Data represent the arithmetic means ± SD from four to eight mice of each genotype.
Mentions: We also examined whether loss of Apaf-1 had an effect on the preneoplastic B cell phenotype induced by Eμ-myc transgene expression. This was done by measuring total leukocyte numbers and numbers of B lymphocytes in blood, bone marrow, spleen, and lymph nodes in mice reconstituted with Eμ-myc/Apaf-1+/+ or Eμ-myc/Apaf-1−/− fetal liver cells 12 wk after transplantation (range = 5–27, and median and mean = 12 wk), an earlier time than most reconstituted mice succumbed to lymphoma (range = 5–77, median = 27, and mean = 31 wk). Absence of significant numbers of tumor cells in all mice used for these analyses was proven by showing that transplanting 106 spleen cells into nonirradiated histocompatible mice did not cause lymphoma (unpublished data). No differences in pre–B cell (B220+sIgM−) or B cell (B220+sIgM+) numbers were found between mice reconstituted with Eμ-myc/Apaf-1+/+ or Eμ-myc/Apaf-1−/− stem cells (Fig. 5). As previously reported (Langdon et al., 1986), Eμ-myc expression caused a reduction in numbers of mature B cells in bone marrow compared with wild-type mice; this is thought to be a consequence of the proapoptotic and differentiation inhibiting effects of myc in B lymphocytes.

Bottom Line: Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors.Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas.Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.

ABSTRACT
Based on experiments with cultured fibroblasts, the apoptosis regulators caspase-9 and Apaf-1 are hypothesized to function as tumor suppressors. To investigate their in vivo role in lymphomagenesis, an IgH enhancer-driven c-myc transgene was crossed onto Apaf-1(-/-) and caspase-9(-/-) mice. Due to perinatal lethality, Emu-myc transgenic Apaf-1(-/-) or caspase-9(-/-) fetal liver cells were used to reconstitute lethally irradiated recipient mice. Surprisingly, no differences were seen in rate, incidence, or severity of lymphoma with loss of Apaf-1 or caspase-9, and Apaf-1 was not a critical determinant of anticancer drug sensitivity of c-myc-induced lymphomas. Moreover, loss of Apaf-1 did not promote oncogene-induced transformation of mouse embryo fibroblasts. Thus, Apaf-1 and caspase-9 do not suppress c-myc-induced lymphomagenesis and embryo fibroblast transformation.

Show MeSH
Related in: MedlinePlus