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1.
Figure 2

Figure 2. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Phenotypic analysis of BCR/ABL-mediated B-ALL. Representative analysis for recipients of p210BCR/ABL expressing Lin cells from a p19ARF-null background. Animals were killed approximately 2 to 3 weeks after transplantation when there were significant signs of illness. Leukocytes from bone marrow and spleen of naive control (CTL) recipient mice were harvested for flow cytometric lineage analysis. FACS plots show comparison of (A) the expression of B220, IgM, and (B) the expression of AA4.1, CD19 between CTL mice, EGFP+ and EGFP populations of recipient mice. The gates in panel A separate IgMhi and IgMlo∼neg expressing B cells.

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
2.
Figure 1

Figure 1. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Comparison of CML and lymphoid blast crisis models. Lin cells from bone marrow of wild-type, p16INK4A/p19ARF-null, or p19ARF-null donors were isolated as described in “Generation of murine models.” The cells were transduced with vectors coexpressing p210BCR/ABL and EGFP, followed by injection into sublethally irradiated wild-type recipient mice. Leukocytes from peripheral blood of the recipients were collected for lineage and morphological analysis approximately 2 to 3 weeks after transplantation. (A) Expression of p210BCR/ABL in wild-type donors resulted in the development of CML-like disease in recipients. Histological staining of peripheral blood shows mature granulocytes (G), FACS analysis indicates that almost all EGFP+ cells are Mac1+/Gr1+. (B) Injection of p210BCR/ABL-expressing cells from p16INK4A/p19ARF or p19ARF-null donors showed high levels of immature lymphoblasts (LBs) in recipient mice. The immunophenotype of EGFP+ cells is almost entirely B220+/CD19+, indicating the disease type is B-lineage acute lymphoblastic leukemia (B-ALL).

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
3.
Figure 4

Figure 4. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Defining the developmental stages of B-ALL–initiating events. HSCs, CLP, proB, and preB cells from p19ARF-null bone marrow were flow sorted and transduced with vectors coexpressing p210BCR/ABL and EGFP, followed by transplantation into sublethally irradiated wild-type recipients. (A) Peripheral blood of recipient mice was sampled at day 17 after transplantation for histological (top row) and flow cytometric analyses to assess the GFP expression and lineage distribution of leukocytes (center and bottom rows). (B) At day 23 after transplantation, bone marrow cells from the p19ARF-null HSC primary recipients were flow sorted into 3 distinct cell groups, (1) B-lymphoid marker positive, (2) myeloid marker positive, and (3) lineage negative, followed by transplantation into sublethally irradiated secondary wild-type recipients. The plot shown was gated on EGFP+ and T-cell negative (CD3) cell population. (C) Outcome of the secondary recipients that received different sorted cells from p19ARF-null HSC primary recipients indicated in panel B.

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
4.
Figure 3

Figure 3. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Disease-onset kinetics and clonal patterns of B-ALL derived from wild-type versus p19ARF-null pro-B cells. Pro-B cells from wild-type and p19ARF-null bone marrow were flow sorted and transduced with vectors coexpressing p210BCR/ABL and EGFP, followed by transplantation into sublethally irradiated wild-type recipients. (A) Kaplan-Meier analysis of survival for the recipients of p19ARF-null (solid line) and wild-type (dashed line) proB cells. (B) Peripheral blood from recipients of p19ARF-null (solid lines, closed symbols) and wild-type (dashed lines, open symbols) proB cells were sampled starting on approximately 10 to 14 days after transplantation and continued approximately every 5 to 10 days until the mice succumbed to B-ALL. The percentage of EGFP+ leukocytes was measured by flow cytometric analysis. (C) Spleen DNA of naive control (lane 1), 5 recipients of p19ARF-null proB (lanes 2-6) and 4 recipients of wild-type pro-B (lanes 7-10) was digested with EcoRI and hybridized with an EGFP probe for Southern blot analysis to reveal the proviral integration pattern.

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
5.
Figure 7

Figure 7. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

In vitro drug response of B-ALL arising from p19ARF-null HSCs versus pro-B cells. Primary recipients injected with p210BCR/ABL-expressing p19ARF-null HSC or pro-B cells were killed approximately 2 to 3 weeks after transplantation. EGFP+ B-ALL (B220+, CD19+, IgM) cells were isolated by FACS and cultured in vitro (IMDM + 10% FBS + 55 micromolar 2-ME, no cytokines) for 2 to 3 weeks. Cells were then treated with dexamethasone (A,B) or imatinib mesylate (C,D) at the concentrations indicated, 106 cells per mL. After 48 hours of treatment, half of each sample was stained with PE-conjugated anti–annexin V antibody and 7AAD to evaluate apoptotic response by flow cytometry. Results are presented as percent of survival relative to untreated control (A,C). A small portion of each culture was plated in methycellulose medium (with murine SCF, IL-3, IL-6, Flt3 ligand, and IL-7) to evaluate the clonal potential of residual cells. Results are presented as percent of colonies relative to untreated control (B,D). Significance was determined with Student paired, 1-tailed t test (****P < .001; ***P < .005).

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
6.
Figure 5

Figure 5. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Phenotypic analyses of B-ALL arising from p19ARF-null HSC versus pro-B cells. Primary recipients injected with p210BCR/ABL-expressing p19ARF-null HSC or pro-B cells were killed approximately 2 to 3 weeks after transplantation. Leukocytes from the recipients' bone marrow were harvested for flow cytometric phenotypic analysis. (A) Cells derived from HSC (left) contained approximately 3-fold more (2.1% vs 0.7%) mature B cells (IgM+) as cells derived from pro-B stage (right). The plots shown were gated on EGFP+ lymphocytes. (B) EGFP+ B-ALL cells (B220+, CD19+, IgM) derived from HSCs (shaded in gray) showed significantly higher CD49e (VLA5) expression than the cells arising from pro-B (white area). (C) 106 flow-sorted EGFP+ B-ALL cells from bone marrow of both HSC and pro-B recipients were reverse-transcribed to cDNA and analyzed by real-time quantitative PCR. Results are shown for 3 independent experiments, with each bar representing the average of triplicates. Error bars are standard deviation. Each gene expression value is shown relative to expression of hypoxanthine-guanine phosphoribosyl transferase (HPRT). Significance was determined with Student paired, 1-tailed t test (*P < .05; **P < .01; ***P < .005; ****P < .001).

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.
7.
Figure 6

Figure 6. From: The biologic properties of leukemias arising from BCR/ABL-mediated transformation vary as a function of developmental origin and activity of the p19ARF gene.

Assessments of clonal and growth potential of B-ALL arising from p19ARF-null HSC versus pro-B cells. Primary recipients injected with p210BCR/ABL-expressing p19ARF-null HSC or pro-B cells were killed approximately 2 to 3 weeks after transplantation. EGFP+ B-ALL (B220+, CD19+, IgM) cells from bone marrow were isolated by FACS for analyses. (A) B-ALL cells were directly sorted into semi-solid methycellulose medium (with murine SCF, IL-3, IL-6, Flt3 ligand, and IL-7), 500 cells per well, and colonies were scored 2 weeks later. Significance was determined with Student paired, one-tailed t test (****P < .001). (B) Photographs of colonies (100× magnified) grown from cultures in panel A. (C) B-ALL cells were directly sorted into U-bottom 96-well culture plate, 1 cell per well, 5 plates per group, with 100 μL culture medium (IMDM + 10% FBS + 55 μM 2-ME). Cell clones that arose from each well were scored 2 weeks later. Significance was determined with Student paired, one-tailed t test (*P < .05). (D) Fresh isolated B-ALL cells from both groups were transplanted into sublethally irradiated wild-type secondary recipients (6 per group) at a dose of 5000 cells per mouse. Results are presented as Kaplan-Meier analysis to compare the survival of recipients that engrafted with B-ALL arising from p19ARF-null HSC and pro-B cells. Significance was determined with survival analysis method of Prism software (*P < .05).

Pin-Yi Wang, et al. Blood. 2008 November 15;112(10):4184-4192.

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