Fig. 3: Treatment resistance in ETP-ALL is associated with a BMP-like population.
a, Selection of ten high-MRD and ten MRD-negative (control) participants from n = 123 participants with ETP-ALL diagnosed within COG AALL0434. b, OS of n = 10 high-MRD versus n = 10 MRD-negative participants profiled using single-cell genomics. The P value for the log-likelihood statistic of a Cox proportional hazard test with day 29 MRD as a covariate is shown. c, Proportion of non-cycling (G1: MRD-negative, n = 23,913 cells; high-MRD, n = 25,727 cells), cycling (S: MRD-negative, n = 2,862 cells; high-MRD, n = 2,274 cells) and dividing (G2M: MRD-negative, n = 6,125 cells; high-MRD, n = 5,499 cells) cells in n = 10 high-MRD versus n = 10 MRD-negative participants. The chi-squared test statistic and P value were computed by comparing the proportion of cells in the G1 versus non-G1 phase in each group (n = 3,500 cells per participant, 33,500 cells per group). d,e, Arrest states of leukemic cells from n = 10 high-MRD and n = 10 MRD-negative participants with ETP-ALL based on projection to the healthy scRNA-seq (left) and scATAC-seq (right) reference trajectory: proportion ranges from 0 to 0.3 (d) and from 0 to 0.5 (e). The D values from a two-sample Kolmogorov–Smirnov (K–S) test are indicated by the brackets (*P < 2.2 × 10−16; n = 25 participants with ETP-ALL: n = 6 induction failure, n = 4 high risk, n = 7 intermediate risk and n = 3 low risk). f, Proportion of ETP blasts in BMP-like and T-specified (T-spec) developmental stages in n = 25 single-cell-sequenced participants with ETP-ALL. The P values from two-sided t-tests are shown above the brackets. Alive indicates participants (n = 16/25) who were alive at last known follow-up (mean = 2,091 days). No event indicates participants (n = 13/25) who had no event at last known follow-up (mean = 2,108 days). g, Proportions of BMP-like blasts in n = 25 single-cell-sequenced ETP-ALL blasts were stratified into high (n = 11 participants) and low (n = 14 participants) using k-means clustering. h, Stratification of n = 25 single-cell-sequenced participants with ETP-ALL by BMP-like proportion (high: >30%, n = 11; low: <30%, n = 14) determined through k-means clustering (k = 2). i, DE surface markers between BMP-like blasts from non-responding participants and T-specified blasts from responding participants. The input matrix to DE analysis was a matrix of G1-phase ETP-ALL blasts with an equal number of cells per participant (n = 1,711 cells per participant and n = 42,775 cells in total). j, DEGs between BMP-like blasts from non-responding participants and T-specified blasts from responding participants. The input matrix to DE analysis was a matrix of G1-phase ETP-ALL blasts with an equal number of cells per participant (n = 1,711 cells per participant and n = 42,775 cells in total). k,l, Normalized gene (k) and surface marker (l) expression for DE BMP-like genes across cell subpopulations in T-ALL, AML, MPAL and healthy donors (HD). Cells were randomly downsampled to n = 200 in each comparison group. m, Stratification of n = 113 participants with ETP from AALL0434 using 119 DEGs between BMP-like and T-specified blasts obtained in d. The prognostic value of the BMP-like signature (BMP-DE-sig) 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 a covariate. Left: stratification with signature alone. Right: stratification with signature and EOI MRD status.
