Figure 1
Insertion mutagenesis screen accelerates leukemia in experimental mice. (A) Mll-AF9/+ mice on a C57BL/6 genetic background were crossed to WT mice of the 129/SvJ genetic background to generate experimental cohorts. The resulting pups were infected by IP injection and followed for disease progression. Mice were killed when moribund, and tissues were collected for cloning insertions, FACS analysis, and histology. (B) Log-rank (Mantel-Cox) tests performed on a Kaplan-Meier survival plot indicate that infected Mll-AF9 mice develop disease with a reduced latency compared with infected WT mice (P < .0001) and noninfected Mll-AF9 mice (P < .0001). A total of 279 mice were used in the study: infected WT (n = 114), infected Mll-AF9 (n = 97), noninfected WT (n = 40), and noninfected Mll-AF9 (n = 28). (C) Infected WT animals develop mostly lymphoid leukemia and Mll-AF9/+ animals develop mostly myeloid leukemia. Pie charts depict the percentage of each leukemia type in the experimental cohorts. Myeloid disease is displayed in red, both myeloid and lymphoid disease is blue, only lymphoid disease is orange, and other diseases are yellow. Lymphoid disease is further divided into L-1 (green) and L-2 (purple). A high CD4 or CD8 population characterizes both L-1 and L-2 but L-2 also has Mac1 positively on its surface. (D) Disease phenotype in MLL-AF9 mice infected with retrovirus. Mouse 410 showed myeloid predominance with differentiated forms in marrow (i) and spleen (not shown): myeloid neoplasm common in Mll-AF9 mice. Mouse 529 showed immature myeloid forms in marrow (ii), infiltrate in the liver (iii), lymphoma in the thymus (iv), and a mixture of myeloid leukemia and lymphoma in the spleen (flow immunophenotype shown in supplemental Figure 3B): mixed AML and T-cell lymphoma/leukemia. Mouse 522 showed moderate myeloid differentiation in the marrow (v), infiltrate in the liver (vi), and myeloid leukemia in the spleen (flow immunophenotype shown in supplemental Figure 3C): AML. H&E. IHC of mouse 539 shows CD3 (vii) and myeloperoxidase (viii) positivity in infiltrating cells in the liver; chromogen is DAB. Scale bar represents 20 μm in subpanels i, ii, iv, and v; 50 μm in iii and vi; and 100 μm in vii and viii. Image acquisition details can be found in supplemental Methods.

Insertion mutagenesis screen accelerates leukemia in experimental mice. (A) Mll-AF9/+ mice on a C57BL/6 genetic background were crossed to WT mice of the 129/SvJ genetic background to generate experimental cohorts. The resulting pups were infected by IP injection and followed for disease progression. Mice were killed when moribund, and tissues were collected for cloning insertions, FACS analysis, and histology. (B) Log-rank (Mantel-Cox) tests performed on a Kaplan-Meier survival plot indicate that infected Mll-AF9 mice develop disease with a reduced latency compared with infected WT mice (P < .0001) and noninfected Mll-AF9 mice (P < .0001). A total of 279 mice were used in the study: infected WT (n = 114), infected Mll-AF9 (n = 97), noninfected WT (n = 40), and noninfected Mll-AF9 (n = 28). (C) Infected WT animals develop mostly lymphoid leukemia and Mll-AF9/+ animals develop mostly myeloid leukemia. Pie charts depict the percentage of each leukemia type in the experimental cohorts. Myeloid disease is displayed in red, both myeloid and lymphoid disease is blue, only lymphoid disease is orange, and other diseases are yellow. Lymphoid disease is further divided into L-1 (green) and L-2 (purple). A high CD4 or CD8 population characterizes both L-1 and L-2 but L-2 also has Mac1 positively on its surface. (D) Disease phenotype in MLL-AF9 mice infected with retrovirus. Mouse 410 showed myeloid predominance with differentiated forms in marrow (i) and spleen (not shown): myeloid neoplasm common in Mll-AF9 mice. Mouse 529 showed immature myeloid forms in marrow (ii), infiltrate in the liver (iii), lymphoma in the thymus (iv), and a mixture of myeloid leukemia and lymphoma in the spleen (flow immunophenotype shown in supplemental Figure 3B): mixed AML and T-cell lymphoma/leukemia. Mouse 522 showed moderate myeloid differentiation in the marrow (v), infiltrate in the liver (vi), and myeloid leukemia in the spleen (flow immunophenotype shown in supplemental Figure 3C): AML. H&E. IHC of mouse 539 shows CD3 (vii) and myeloperoxidase (viii) positivity in infiltrating cells in the liver; chromogen is DAB. Scale bar represents 20 μm in subpanels i, ii, iv, and v; 50 μm in iii and vi; and 100 μm in vii and viii. Image acquisition details can be found in supplemental Methods.

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