The individual tumors showed significant differences in occurrence between, between MtaplacZ/+ and Mtap+/+ animals, however, there was a significant difference between MtaplacZ/+ and Mtap+/+ in the percentage of necropsied animals in which no lesion was detected (16 vs. 69 , P = 0.0001). These results show that heterozygosity for Mtap decreases survival in Pten+/2 animals.MtaplacZ/+ Increases Grade, Proliferative Capacity, and Odc Expression in Em-myc MiceWe next characterized the pathology of the lymphomas in Emmyc mice. First, we examined thymus Clavulanate (potassium) chemical information sections from control, Em-myc Mtap+/+, and Em-myc MtaplacZ/+ animals for a variety of morphological and immunohistochemical features. As expected, staining with anti-bodies to either CD3 (T-cell marker) or CD45R/B220 (B-cell marker) indicated that all the lymphomas in both Em-myc Mtap+/+ and Em-myc Mtap +/2 animals were B-cell neoplasms (not shown). Morphologically, these lymphomas exhibited a spectrum between large cells, with irregular nuclear membranes, vesicular chromatin, and prominent nucleoli (diffuse large B-cell lymphoMtap Accelerates Tumorigenesis in MiceTable 1. Tumor formation and death in Mtap Pten animals.MtaplacZ/+/Pten+/16/32a (50 ) (325 days) Spontaneous death (autolysis)(Arg8-vasopressin median age) (median age) 11/32b (34.37 ) (308 days)aEvent Tumor formation determined by necropsy (median age)Mtap+/+/Pten+/9/32a (28.8 ) (367 days) 1/32b (3.12 ) (422 days)bMtaplacZ/+ vs. Mtap+/+, P = 0.125. MtaplacZ/+ vs. Mtap+/+, P = 0.0027. doi:10.1371/journal.pone.0067635.tma-like) to others with medium sized cells, relatively fine chromatin and small nucleoli with brisk mitotic activity and apoptosis resembling Burkitt’s lymphoma. Some fell in between resembling “grey zone” lymphoma (Fig. 2A). These features were graded from grade 1 for “no tumor” to grade 6 for the high-grade Burkitt-like lymphoma. Grading of all the samples show that, in general, the tumors observed in Em-myc Mtap +/2 are of a higher grade than those in Em-myc Mtap+/+ (Fig. 2C). The proliferation marker Ki67 was also examined and scored blindly, and it was found that there were increased numbers of strongly staining cells (up to almost 100 ) in Em-myc MtaplacZ/+ animals (Fig. 2B?C). Because loss of MTAP was associated with increased ODC activity in other settings, we 23148522 stained thymus sections with an anti-body to mouse ODC. We observed both a higher percentage of cells expressing ODC and increased intensity of staining in the lymphomas from MtaplacZ/+ compared to Mtap+/+ animals (Fig. 2B?C). These findings show that the B-cell lymphomas in Em-myc MtaplacZ/+ animals tend to be of higher grade and have elevated ODC expression compared to Em-myc Mtap+/+ animals.CD45R/B220 and high AA4.1 (CD93) expression and negative for CD5 and CD3, indicating that they are early stage B-cells, either surface IgM2 or IgM+, in both Mtap+/+ and MtaplacZ/+ mice. All AA4+ IgM+ cells were IgDlo or IgD2, CD24++, CD212, CD232, in further agreement with their immature B cell stage. All IgM2 cells failed to show significant TdT mRNA levels, in contrast to the tight TdT (Terminal deoxynucleotidyl Transferase) expression by the pro B cells [34], and all expressed low levels of cytoplasmic IgM and high surface PNA expression, consistent with pre-B cell stage [41]. Low cytoplasmic IgM level excluded the possibility of IgM2 plasmacytoma. Taken together, our data show that the cell of origin of the lymphomas was most likely started from the pre-B stage of developme.The individual tumors showed significant differences in occurrence between, between MtaplacZ/+ and Mtap+/+ animals, however, there was a significant difference between MtaplacZ/+ and Mtap+/+ in the percentage of necropsied animals in which no lesion was detected (16 vs. 69 , P = 0.0001). These results show that heterozygosity for Mtap decreases survival in Pten+/2 animals.MtaplacZ/+ Increases Grade, Proliferative Capacity, and Odc Expression in Em-myc MiceWe next characterized the pathology of the lymphomas in Emmyc mice. First, we examined thymus sections from control, Em-myc Mtap+/+, and Em-myc MtaplacZ/+ animals for a variety of morphological and immunohistochemical features. As expected, staining with anti-bodies to either CD3 (T-cell marker) or CD45R/B220 (B-cell marker) indicated that all the lymphomas in both Em-myc Mtap+/+ and Em-myc Mtap +/2 animals were B-cell neoplasms (not shown). Morphologically, these lymphomas exhibited a spectrum between large cells, with irregular nuclear membranes, vesicular chromatin, and prominent nucleoli (diffuse large B-cell lymphoMtap Accelerates Tumorigenesis in MiceTable 1. Tumor formation and death in Mtap Pten animals.MtaplacZ/+/Pten+/16/32a (50 ) (325 days) Spontaneous death (autolysis)(median age) (median age) 11/32b (34.37 ) (308 days)aEvent Tumor formation determined by necropsy (median age)Mtap+/+/Pten+/9/32a (28.8 ) (367 days) 1/32b (3.12 ) (422 days)bMtaplacZ/+ vs. Mtap+/+, P = 0.125. MtaplacZ/+ vs. Mtap+/+, P = 0.0027. doi:10.1371/journal.pone.0067635.tma-like) to others with medium sized cells, relatively fine chromatin and small nucleoli with brisk mitotic activity and apoptosis resembling Burkitt’s lymphoma. Some fell in between resembling “grey zone” lymphoma (Fig. 2A). These features were graded from grade 1 for “no tumor” to grade 6 for the high-grade Burkitt-like lymphoma. Grading of all the samples show that, in general, the tumors observed in Em-myc Mtap +/2 are of a higher grade than those in Em-myc Mtap+/+ (Fig. 2C). The proliferation marker Ki67 was also examined and scored blindly, and it was found that there were increased numbers of strongly staining cells (up to almost 100 ) in Em-myc MtaplacZ/+ animals (Fig. 2B?C). Because loss of MTAP was associated with increased ODC activity in other settings, we 23148522 stained thymus sections with an anti-body to mouse ODC. We observed both a higher percentage of cells expressing ODC and increased intensity of staining in the lymphomas from MtaplacZ/+ compared to Mtap+/+ animals (Fig. 2B?C). These findings show that the B-cell lymphomas in Em-myc MtaplacZ/+ animals tend to be of higher grade and have elevated ODC expression compared to Em-myc Mtap+/+ animals.CD45R/B220 and high AA4.1 (CD93) expression and negative for CD5 and CD3, indicating that they are early stage B-cells, either surface IgM2 or IgM+, in both Mtap+/+ and MtaplacZ/+ mice. All AA4+ IgM+ cells were IgDlo or IgD2, CD24++, CD212, CD232, in further agreement with their immature B cell stage. All IgM2 cells failed to show significant TdT mRNA levels, in contrast to the tight TdT (Terminal deoxynucleotidyl Transferase) expression by the pro B cells [34], and all expressed low levels of cytoplasmic IgM and high surface PNA expression, consistent with pre-B cell stage [41]. Low cytoplasmic IgM level excluded the possibility of IgM2 plasmacytoma. Taken together, our data show that the cell of origin of the lymphomas was most likely started from the pre-B stage of developme.
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