The ZMIZ1-MYB network of BMP-like enhancers predicts treatment resistance and poor survival in ETP-ALL and ETP-like leukemia. (A and B) Averaged expression of ZMIZ1-5 signature genes (MEF2C, BCL2, MYB, MYCN, and ZMIZ1) (A) and ZMIZ1-ETP-8 signature genes (ZMIZ1-5 genes merged with ETP-TF5 genes—MEF2C, BCL2, MYB, MYCN, ZMIZ1, HHEX, LMO2, and LYL1) (B) in day 29 MRD-negative and MRD-positive ETP/near ETP-ALL patients in the TARGET dataset; n = 16 and 26 respectively; P values were based on Wilcoxon test. (C and D) Kaplan–Meier plots showing overall survival of bulk-RNA-seq ETP-ALL patients in AALL0434 binarized using the ZMIZ1-5 (C) or ZMIZ1-ETP-8 (D) signatures as described in Fig. S1 I. (E–M) UMAP scatter plots (E–I) and boxplots (J–M) from AALL0434 showing T-ALL subtypes (E) and expression Z-scores of ZMIZ1 (F and J), ETP-TF5 (G and K), ZMIZ1-5 (H and L), and ZMIZ1-ETP-8 (I and M) signatures. n = 1,335. P value is the Wilcox test for ETP-like against others. (N–P) Kaplan–Meier plots showing survival of ETP-like patients in AALL0434 binarized using the ETP-TF5 (N), ZMIZ1-5 (O), or ZMIZ1-ETP-8 (P) signatures. (Q) Model of how the ZMIZ-MYB network contributes to multiple cardinal features of high-risk BMP-like ETP-ALL. Potential vulnerabilities through small molecules are highlighted in red. *ZMIZ1 induction by MYB. FFL = feedforward loop. *P < 0.05; **P < 0.01.