Results: 4

1.
Figure 2

Figure 2. From: Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.

Clinical presentation of the hMB model. (A) Kaplan-Meier survival analysis of GFP-control (G; n=9), GFP-BCL2 (GB; n=5), GFP-MYC (GM; n=5) and GFP-MYC-BCL2 (hMB; n=9). (B) Representative image of a control (GFP) and a leukemic hMB spleen at week 12 post injection and corresponding representative low-magnification cross-section of a control (GFP) and a leukemic hMB spleen. (C-F) Histomorphological analysis of leukemic mice. (C) Bone marrow smear (Giemsa-Wright staining). (D) Bone marrow section (H&E staining) with (E) Spleen high magnification showing lymphoma blast cells. (F) Brain section (H&E staining) showing leptomeningeal infiltration by leukemic blasts.

Ilya Leskov, et al. Oncogene. ;32(8):1066-1072.
2.
Figure 3

Figure 3. From: Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.

Flow cytometry analysis of reconstituted mice. (A) Flow cytometry analysis of lymphoma cells from spleens of diseased hMB mice. Splenocytes were stained for hCD45 as well as human CD19, CD10, surface IgM (sIgM), CD20, CD52, surface CD22 (sCD22), IL-7Rα, TdT, cytoplasmic IgM (cyIgM), or cytoplasmic CD79a (cyCD79a). Dot plots show GFP versus the indicated surface staining of hCD45+ cells. Histograms show TdT, IL-7Rα, cyIgM and cyCD79a staining of hCD45+ cells (dark line) versus isotype controls (faint lines). Karyotyping of tumors showing (B) trisomy 7 and (C) an elongation at chromosome 12p. Representative metaphases from a minimum of 22 metaphases per sample are displayed.

Ilya Leskov, et al. Oncogene. ;32(8):1066-1072.
3.
Figure 1

Figure 1. From: Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.

A humanized mouse model of “double-hit” lymphoma. (A) A schematic diagram showing the lentiviral vector in which the human B cell-specific enhancer-promotor controls the expression of GFP, c-MYC, and BCL2, transduction of human hematopoietic stem cells (HSC), and generatioin of humanized mice. The dot-plot shows human CD45 (hCD45) versus murine CD45 (mCD45) staining of peripheral blood mononuclear cells of a representative humanized mouse 9 weeks after reconstitution. (B) Peripheral blood mononuclear cells (PBMCs) from NSG mice injected with lentivirally-transduced human HSCs. Peripheral blood was analyzed for hCD45, mCD45 and GFP 9 weeks after engraftment in GFP, GFP-MYC, GFP-BCL2 and GFP-MYC-BCL2 mice (n=5). Histograms show GFP expression gating on human CD45+ cells indicated in Figure 1A. Murine cells are GFP-negative. Percentages of GFP+ cells are indicated. (C) Time dependent development of B-cell hyperplasia in GFP-BCL2 mice. Sublethally irradiated adult NSG mice were engrafted with human CD133+ cells that had been spin-infected with lentivirus expressing either GFP alone or GFP plus BCL2. At the indicated times following engraftment, PBMCs from these mice were analyzed for GFP expression. All cells were gated on human CD45+ cells. Numbers indicate percent cells in the indicated region. Representative data from at least 5 mice are shown

Ilya Leskov, et al. Oncogene. ;32(8):1066-1072.
4.
Figure 4

Figure 4. From: Rapid generation of human B-cell lymphomas via combined expression of Myc and Bcl2 and their use as a preclinical model for biological therapies.

Therapeutic modeling in the hMB “double-hit” lymphoma model. (A) Secondary transplant mice were treated upon presence of leukemic cells in the peripheral blood at day 21 post transplant (corresponding to day 1 of treatment) with dexamethasone (DEX; 10 mg/kg), doxorubicin (DOX;5 mg/kg), cytarabine (ARA-C;50 mg/kg), total body irradiation (RAD; 5 Gy), cyclophosphamide (CYP; 300 mg/kg ) or alemtuzumab (ALEM; 5 mg/kg). Treatment response was assessed at day 7 post treatment by measuring total number of GFP+ lymphoma cells in the spleen. (B) Comparison of tumor burden in peripheral blood, spleen and brain 8 days after initiating cyclophosphamide treatment. GFP+ lymphoma cells were counted using the C6 flow cytometer (Accuri Cytometers). Each symbol represents one mouse; average and standard error are shown for each group. P values of indicated comparisons are shown (n.s.=non-significant). (C) Kaplan-Meier survival analysis of secondary hMB recipient mice that received intravenous injections of alemtuzumab (Alem., 5 mg/kg) or of vehicle control; 3 injections over 7 days, delivered on days 1, 4, and 7). (D) Comparison of tumor burden in different organs 8 days after initiating alemtuzumab treatment. GFP+ lymphoma cells were counted using the C6 flow cytometer (Accuri Cytometers). Each symbol represents one mouse; average and standard error are shown for each group. P values of indicated comparisons are shown (n.s.=non-significant). (E) Visualization of the in vivo distribution of alemtuzumab 24 hours following injection into either non-reconstituted NSG mice or NSG mice transferred with hMB lymphoma cells. Mice were injected with 5 mg/kg AlexaFluor750-labeled alemtuzumab and distribution of fluorescence assessed after 6h. Representative scans of healthy control vs. lymphoma hMB mice showing enriched signal from spleen and long bones. (F) Alemtuzumab binding to target organs comparing non-transplanted healthy NSG mice to hMB-mice. Brains were dissected from the skull and assessed separately for quantification. Spleens were examined in situ. Photon emission from defined region of interest was quantified for spleen and brain (n=6 each). (G) Flow cytometry analysis of AlexaFLuor750-alemtuzumab binding to GFP+ lymphoma cells in the spleen but not in brain parenchyma and submeningeal space. Cells were directly subjected to flow cytometry after organ dissociation

Ilya Leskov, et al. Oncogene. ;32(8):1066-1072.

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