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. 2019 Apr 9;8:e39380. doi: 10.7554/eLife.39380

Figure 1. Reduced lifespan and increased tumor incidence in Kdm6a F1s.

(A) Cross for Kdm6a F1 and control F1 mice. All Kdm6a cKO (n = 3) and control (n = 2) mice were littermates. (B) Survival curve for Kdm6a F1 and control F1 males. Hazard ratio (HR) and p-value calculated by a Cox proportional hazards model. (C) Raw counts of tumors (p=0.0071) and non-tumor phenotypes (p=0.69) in Kdm6a F1 vs. control F1 males at necropsy (p-values, one-sample test of proportions). (D) Left to right, hematoxylin and eosin (H&E) staining of normal spleen in control F1; H&E of histiocytic sarcoma in spleen of Kdm6a F1, showing diffuse infiltration of red pulp with nuclear pleomorphism and frequent mitotic figures (inset); immunohistochemistry of monocyte-lineage marker F4/80 in spleen histiocytic sarcoma. (E) H&E of representative tumors in Kdm6a F1s (top) and matched normal tissues from control F1s (bottom). Scale bars, 100 um (large images), 10 um (insets). See Figure 1—source data 1.

Figure 1—source data 1. Survival and phenotype of Kdm6a F1s.
elife-39380-fig1-data1.xlsx (37KB, xlsx)
DOI: 10.7554/eLife.39380.014

Figure 1.

Figure 1—figure supplement 1. Normal spermatogenesis in Utx cKO males.

Figure 1—figure supplement 1.

Top, hematoxylin and eosin (H&E) staining of Kdm6a cKO and control adult testes. Bottom, counts of male and female F1 offspring from Kdm6a cKO and control mice. p-value, Fisher's exact test.
Figure 1—figure supplement 2. Efficiency of Ddx4-Cre in the male germ line.

Figure 1—figure supplement 2.

Top, sample genotyping gel for one litter of Kdm6a F1s, showing bands discriminating Kdm6a(+) and Kdm6a(fl) alleles (left) and bands detecting the Kdm6a delta allele (right).
Figure 1—figure supplement 3. Survival of Kdm6a F1s from individual sires.

Figure 1—figure supplement 3.

Top left shows F1s from the two control sires. Other plots show combined control data in grey and data from F1s of individual Kdm6a F1 sires in blue. HR, hazard ratio. p-values calculated using a Cox proportional hazards model.
Figure 1—figure supplement 4. Survival of Kdm6a F1s grouped by presence or absence of the Cre transgene.

Figure 1—figure supplement 4.

'Cre?' indicates failed or ambiguous genotyping. p-values calculated using a Cox proportional hazards model.
Figure 1—figure supplement 5. Contingency table for euthanasia vs.natural death in Kdm6a F1s and control F1s.

Figure 1—figure supplement 5.

Figure 1—figure supplement 6. Utx F1 and control F1 weight and length.

Figure 1—figure supplement 6.

Body weight (p=0.8775) and length (p=0.01578) of male Kdm6a F1s and control F1s at necropsy. p-values calculated by Welch’s t-test.
Figure 1—figure supplement 7. Counts of gross and histopathological diagnoses at necropsy for Kdm6a F1s and control F1s.

Figure 1—figure supplement 7.

Figure 1—figure supplement 8. Tumor rates in control and Kdm6a F1s and F2s broken down by individual sire.

Figure 1—figure supplement 8.

Numbers of F1 or F2 mice are shown above the bar.
Figure 1—figure supplement 9. Characterization of myeloid lineages in F1 bone marrow.

Figure 1—figure supplement 9.

Flow cytometry showing increased fraction of monocyte/macrophage lineage cells in Kdm6a F1 compared to control F1 bone marrow. **p=0.0079 (Mann-Whitney U test).
Figure 1—figure supplement 10. Validation of tumor types in Utx F1s.

Figure 1—figure supplement 10.

Immunohistochemistry (IHC) for sample tumors: VEGF-A (left, cytoplasmic) and ERG (right, nuclear) in angiosarcoma (Figure 2D); TTF-1 in lung adenoma (Figure 1E); Glutamine synthetase in hepatocellular carcinoma (Figure 2D); CD20 (left, tumor cells positive) and CD3 (right, tumor cells negative) in B-cell lymphoma (Figure 2D). Scale bar, 100 um.