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. 2021 Oct 7;3(1):16–31. doi: 10.1158/2643-3230.BCD-20-0216

Figure 5.

Figure 5. Posttranscriptional upregulation of complement component 3 promotes leptomeningeal disease in KMT2A-rearranged xenografts. A, Translation rate measured by OPP incorporation in matched BM and CNS blasts from KMT2A-rearranged patient 11, 12, and 15 xenografts represented as OPP mean fluorescence intensity (MFI) normalized to matched BM mean for each sample; n = 3 mice (patient 11 diagnosis), n = 10 mice (patient 12 diagnosis, patient 15 diagnosis). B, Biological processes upregulated as measured by label-free mass spectrometry proteomics of CNS blasts compared with matched BM blasts shown as a Cytoscape enrichment map with Markov Cluster Algorithm (MCL)-clustered, ClueGO-identified nodes colored by gene ontology process, with node size reflecting the number of involved proteins and lines representing proteins shared between nodes. C, Cytoscape map of pathways upregulated in proteins with greater abundance in CNS blasts without differential RNA-seq counts of the corresponding mRNA compared with BM blasts. Circular nodes represent MCL clustering of ClueGO-identified biological processes, with node size reflecting the number of involved proteins and edges representing proteins shared between nodes. D, Primary B-ALL xenografts were treated with 10 mg/kg of the C3a receptor antagonist SB 290157 or DMSO vehicle biweekly from the week after engraftment to endpoint. E, Human B-ALL engraftment in various tissues from D normalized to vehicle; n = 7 mice per group from patient 12 diagnosis and patient 15 diagnosis. F, Secondary B-ALL BM xenografts were treated with vehicle or 10 mg/kg C3a receptor agonist biweekly from the week after engraftment to endpoint. G, Human B-ALL engraftment in various tissues from F normalized to vehicle control; n = 4 (patient 11 CNS), n = 5 (patient 11 BM and patient 12 BM and CNS), or n = 10 (patient 15) mice per group. H, Mice with established secondary B-ALL BM xenografts were treated with vehicle or 10 mg/kg C3a receptor agonist for 3 days immediately prior to endpoint. I, Human B-ALL CNS engraftment from H normalized to vehicle control. Percentage of human B-ALL cells in CNS xenografts from H positive for Ki-67 (J) or activated caspase-3 (K). n = 5 mice per group in I–K. Bars, mean ± SE; two-sided unpaired t test, with *, P < 0.05; **, P < 0.01; ns, not significant.

Posttranscriptional upregulation of complement component 3 promotes leptomeningeal disease in KMT2A-rearranged xenografts. A, Translation rate measured by OPP incorporation in matched BM and CNS blasts from KMT2A-rearranged patient 11, 12, and 15 xenografts represented as OPP mean fluorescence intensity (MFI) normalized to matched BM mean for each sample; n = 3 mice (patient 11 diagnosis), n = 10 mice (patient 12 diagnosis, patient 15 diagnosis). B, Biological processes upregulated as measured by label-free mass spectrometry proteomics of CNS blasts compared with matched BM blasts shown as a Cytoscape enrichment map with Markov Cluster Algorithm (MCL)-clustered, ClueGO-identified nodes colored by gene ontology process, with node size reflecting the number of involved proteins and lines representing proteins shared between nodes. C, Cytoscape map of pathways upregulated in proteins with greater abundance in CNS blasts without differential RNA-seq counts of the corresponding mRNA compared with BM blasts. Circular nodes represent MCL clustering of ClueGO-identified biological processes, with node size reflecting the number of involved proteins and edges representing proteins shared between nodes. D, Primary B-ALL xenografts were treated with 10 mg/kg of the C3a receptor antagonist SB 290157 or DMSO vehicle biweekly from the week after engraftment to endpoint. E, Human B-ALL engraftment in various tissues from D normalized to vehicle; n = 7 mice per group from patient 12 diagnosis and patient 15 diagnosis. F, Secondary B-ALL BM xenografts were treated with vehicle or 10 mg/kg C3a receptor agonist biweekly from the week after engraftment to endpoint. G, Human B-ALL engraftment in various tissues from F normalized to vehicle control; n = 4 (patient 11 CNS), n = 5 (patient 11 BM and patient 12 BM and CNS), or n = 10 (patient 15) mice per group. H, Mice with established secondary B-ALL BM xenografts were treated with vehicle or 10 mg/kg C3a receptor agonist for 3 days immediately prior to endpoint. I, Human B-ALL CNS engraftment from H normalized to vehicle control. Percentage of human B-ALL cells in CNS xenografts from H positive for Ki-67 (J) or activated caspase-3 (K). n = 5 mice per group in I–K. Bars, mean ± SE; two-sided unpaired t test, with *, P < 0.05; **, P < 0.01; ns, not significant.