Extended Data Fig. 8: Genome-wide mapping of XBP1 gene targets in HSPCs identifies a prognostic 18-gene signature. | Nature Immunology

Extended Data Fig. 8: Genome-wide mapping of XBP1 gene targets in HSPCs identifies a prognostic 18-gene signature.

From: IRE1α–XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs

Extended Data Fig. 8

(a and b) Heatmap of XBP1 binding peaks (a) and normalized (average of replicate samples) read density of aligned DNA at peaks (b) in the HSPC line HPC-7 at baseline (DMSO) and after 6 hours treatment with tunicamycin. (c) Comparison of XBP1-bound genes to TCF4-target genes identified 460 overlapping genes. (d) GSEA plot of the 460 overlapping XBP1 and TCF4 genes from panel (c) in the transcriptome of LSK cells from Ern1koFlt3ITD/ITD compared to Ern1wtFlt3ITD/ITD mice. Upregulation of the 460 genes in IRE1α-deficient LSK cells suggest that these genes are repressed by XBP1 after IRE1α activation. (e and f) ENRICHR pathway analysis (e) and heatmap of expression of the leading edge 106 (among 460 total identified in panel c) XBP1-bound genes in HSPCs that are also TCF4-targets. (g) Integrated analysis of XBP-1 bound genes with significantly (Log2 fold change >1, P < 0.05) upregulated (“UP”) genes in Ern1koFlt3ITD/ITD LSK cells. The overlapping 132 genes from this integration were compared to TCF4 target genes in colorectal cancer cells, yielding an “18-gene” signature. Heatmap of expression of these 18 genes in Ern1wtFlt3ITD/ITD and Ern1koFlt3ITD/ITD LSK cells is shown in Fig. 7a. (h and i) Kaplan-Meier graphs and Multivariate Cox analysis (tables) of event-free survival of patients in the GSE14468 cohort (h) and overall survival of patients in the BEAT-AML cohort (i). P, Mantel-Cox Log-rank test.

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