Extended Data Fig. 10: Computational and in vitro drug screening results against BMP-like blasts.
(a) Top predicted drugs from LINCS1000 (n = 10). BMP-like DEGs (High Risk) and T-specified DEGs (Low Risk) were inputted into LINCS1000. Drug treated leukemia cell lines were filtered for statistical significance (FDR < 0.1) and connectivity score (NCS > 0.8). Drugs are ranked by number of leukemia cell lines with favorable transcriptomic shift after treatment (downregulation of BMP-like DEG, upregulation of T-specified DEG). Each drug is colored by the mean -log(FDR). (b) Top leukemia specific targets (n = 6) predicted from DepMap screening. Dependency scores in leukemic (n = 59) and non-leukemic cell lines (n = 1,052) were calculated for all BMP-like DEGs and ranked by fold change in dependency (mean dependency in leukemia / mean dependency in non-leukemia cell lines). The top druggable (with score 1+ from other drug databases) targets are shown. (c) Top druggable targets (n = 6) from TTD/DrugIDB drug database screening. Targets are ranked by percentage expression and selected based on Log2FC > 1. An example of drug is listed below the target. (d) Top 10 targets by aggregate database (1-5) and DE (1-3) score. (e) Drugs active in n = 4/4 ETP patients tested with mean IC50. Drugs with marked asterisk had IC50 below lowest tested dose in 1 sample. n = 40 drugs, n = 9 ETP-active. (f) Drugs active in some, but not all ETP patients. High MRD patients are colored in red. n = 40 drugs, n = 8 partially active. (g) Correlations between drug sensitivity (-log2 of the IC50 concentration) and the scRNA-seq derived BMP-like percentage (top) and the BMP-like signature score computed using n = 119 differentially expressed genes on bulk RNA-sequenced data (bottom). The bulk RNA-seq correlations (bottom) include the data from this study (n = 10) and data by Lee et al. Total number of data points for each drug is indicated in the figure. Spearman’s correlations and significance are shown. (h) Gene expression of ibrutinib targets across ETP subtypes, BMP-like/T-specified blast phenotypes, and stages of healthy T cell development. Dot size indicates percent of cells with gene expression detected, and color indicates normalized average expression. (n = 328,820 cells; T-ALL patients: n = 271,603 cells; Healthy Control: n = 49,623 cells). (i) Representative flow gating for quantification of hCD7 + hCD45+ leukemic blasts during venetoclax or control treatment. (j) peripheral blast percentage (left) and log2 fold change (right) of peripheral blast % over study period for PAUNDK (BMP-low, n = 8: n = 4 control, n = 4 venetoclax) PDX model during control or venetoclax treatment. P-value from two-sided t-test is shown. (k) Bone Marrow (BM, top) and spleen (bottom) leukemic burden in High-BMP (left, n = 6:: n = 3 control, n = 3 venetoclax) and low-BMP (right, n = 8: n = 4 control, n = 4 venetoclax) PDX models after 1 month of venetoclax or vehicle (ctrl) treatment. P-value from two-sided t-test is shown. The box includes the median, hinges mark the 25th and 75th percentiles, and whiskers extend 1.5 times the interquartile range. (l) Peripheral blast percentage (left) and log2 fold change (right) of peripheral blast % over study period for PATTDP (BMP-high, n = 6: n = 3 control, n = 3 venetoclax) PDX model during control or venetoclax treatment. P-value from two-sided t-test is shown. (m) Fold-reduction of leukemic burden in BM and spleen with venetoclax treatment in BMP-high (n = 6) and BMP-low (n = 8) PDX models.
