Extended Data Fig. 2: TCF7/LEF1 activation underlies CD5 expression in Near-ETP T-ALL and contributes to positive outcome in ETP-ALL Patients.
(a) Overall survival of ETP, Near-ETP and Non-ETP patients from Children’s Oncology Group AALL0434 cohort (n = 1411). (b) Differentially expressed surface markers, genes, and transcription factors in single-cell sequenced ETP (n = 25) and Near-ETP (n = 5) patients. (c) Intersection of differentially expressed transcription factors and differentially accessible motifs in single-cell sequenced ETP (n = 25) and Near-ETP (n = 5) patients. (d) Expression of TCF7 and LEF1 and accessibility of TCF7 and LEF1 motifs in healthy T-cell development references. n = 1200 cells; n = 100 randomly downsampled cells per group. (e-g) Subset of transcriptional regulatory network constructed using integrated scRNA and scATAC data from (e) ETP-ALL (n = 25), (f) Near-ETP ALL (n = 5), and (g) Non-ETP ALL (n = 10) patients. Transcription factors are represented as squares, gene targets as ovals. In (e), color is proportional to expression fold change in comparison to Near-ETP and Non-ETP blasts. In (f-g), color is proportional to expression fold change in comparison to ETP blasts blue is downregulated, red upregulated. In (e), edges with > 100 edge score are shown, with edge score representing the sum of -log(p-value) of all predicted EP interactions. In (f-g), Edges contacting TCF7 and LEF1 with regression coefficient > 0.3 are shown. Predicted regulators of TCF7 and LEF1 are highlighted. (h) Signature score of top 28 target genes of the TCF7/LEF1 regulon and top 11 predicted TF regulators of TCF7/LEF1/CD5 in bulk-sequenced ETP (n = 110) and Near-ETP (n = 168) T-ALL patients from COG AALL0434 trial. The box includes the median, hinges mark the 25th and 75th percentiles, and whiskers extend 1.5 times the interquartile range. (i-k) Kaplan-Meier plot showing overall survival of bulk-RNA-sequenced ETP-ALL (n = 110) and Near-ETP (n = 168) patients in AALL0434 binarized using the TCF7-LEF1 targets and activator signature. Prognostic value of the TCF7/LEF1 signature in multivariate analysis (with Day 29 MRD, CNS status, WBC count, and age at diagnosis) is shown below the Cox-proportional hazard log-likelihood p-value with Day 29 MRD as covariate.
