Zmiz1 binds a native stem cell enhancer (NMRE) that interacts extensively with Mycn in BMP and BMP-like ETP-ALL cells. (A) ChIP-seq, HiChIP, and ATAC-seq profiles in BMP-like (CUTLL3; LOUCY) and near ETP-ALL (THP-6) cell lines within the TAD (merged from four ETP-ALL patient samples and flanked by “L” and “R” CTCF sites) that contains the MYCN gene (GSE134671). The red box highlights the unannotated NMRE at +540 kb from the MYCN gene. (B) RNA-seq transcriptome profile at the MYCN locus across ETP-ALL (purple) and T-ALL (blue) patients. Red box indicates NMRE. (C) Correlation plots of the expression of NMRE versus MYCN (left) or FAM49A (right) across 34 patients characterized by ETP-ALL gene signature (EGAS00001004810). The bottom panel represents the RNA-seq profile of the MYCN locus with positions of the indicated transcripts in a representative ETP-ALL sample (LOUCY). (D) Virtual 4-C on Hi-C at the MYCN locus showing the average normalized tracks from ETP-ALL (n = 3) and mature T-ALL (n = 4) patients (GSE115893). Viewpoint (star) is set on MYCN. Red box represents the NMRE location. (E) 4C-seq profiles of BMP-like ETP-ALL model (LOUCY, in green) and mature T-ALL model (CUTLL1, in purple). Stars indicate the viewpoint, located either on the MYCN gene (upper panel) or on the NMRE (lower panel). The yellow profile indicates the strength of interactions (counts) related to the corresponding viewpoint. (F) Hi-C interaction heatmaps of representative ETP-ALL cases (red), HSPC (green), and mature T cells (purple). Black arrows indicate the MYCN–NMRE interaction. The plot on the right correlates intra-TAD activity (average of the normalized interaction scores for all interactions within the MYCN TAD [Kloetgen et al., 2020]) and MYCN expression in primary human cell types. (G) ATAC-seq profiles of the NMRE in sorted human CD34⁺Lin⁻ cord blood (HSPC) and thymocytes from two donors (D1 and D2). GSE151075. ETP/DN2 = CD34⁺CD1⁻CD4⁻; DN3/DN4 = CD34⁺CD1⁺CD4⁻; ISP = CD28⁺CD4⁺CD3⁻CD8⁻ DP = CD4⁺CD8⁺. (H) ATAC-seq profiles of the NMRE in sorted mouse BM progenitors and thymocytes (Immgen). (I) Hi-C interaction heatmaps of different stages of murine BM progenitor and T-cell development (GSE79422). The blue box represents the TAD enclosing Mycn and NMRE. Lower panel shows the correlation of Mycn-NMRE interactivity and Mycn expression across developmental stages.