Fig. 1: Indisulam resistance in transgenic MYCN/ALKF1178L mouse models is associated with lineage switch to cell states with MES and Schwan precursor cells.
From: RBM39 degrader invigorates innate immunity to eradicate neuroblastoma despite cancer cell plasticity
a Tumor growth curve for MYCN/ALKF1178L mice treated with 25 mg/kg of indisulam. Blue indicates sustained complete response (biological replicates n = 3). Pink indicates indisulam resistance and relapse (biological replicates n = 2). b Ultrasound imaging of tumor relapse. Top panel shows the two-dimensional ultrasound images over time and the bottom panel shows the volume reconstructions. c GSEA plot analysis of naïve (biological replicates n = 2) vs relapsed tumors (biological replicates n = 2). The normalized RNA read counts are transformed to log2 counts per million reads (log2CPM) for GSEA analysis. Right y-axis =one-sided, nominal p-values. Left y-axis = false discovery rate (FDR) q values. X-axis = normalized enrichment score (NES). d GSEA shows “20q11 amplicon” gene set upregulated in indisulam-resistant tumors. Nominal p-value < 0.0001 calculated by one-sided Fisher’s exact test. e The normalized RNA-seq reads at Rbm39 gene locus by IGV program. f Western blot analysis for vehicle-treated tumors (biological replicates n = 3) and indisulam-resistant tumors (biological replicates n = 2). The experiment was done once. g Pearson correlation between gene copy number vs indisulam response from DepMAP data (www.depmap.org). p-value (left y-axis, two-sided) calculated using t-distribution based on the Pearson correlation coefficient (x-axis). The z-score calculated by permutation test. h Pearson correlation between gene expression vs indisulam response from DepMAP data (www.depmap.org). The p value is calculated using two-sided t-distribution. Y-axis = expression of RBM39 with log2TMP plus 1 (TPM + 1). X-axis = log2 fold change of indisulam in cell viability measurement. GSEA shows “neural stem cell” (i) and “NBL_MES” (j) gene sets significantly upregulated in resistant tumors. Nominal p value < 0.0001 calculated by one-sided Fisher’s exact test. k Heatmap shows the expression of Schwan cell progenitor (SCP) markers in naïve (biological replicates n = 2) vs. relapsed tumors (biological replicates n = 2). The Morpheus program is used to generate z-score-based interactive heatmap after log2-transformed expression data. l Sox10 labels the SCP cell population from the study9. Source data are provided as a Source Data file.
