rap1 inhibitor  (Tocris)

Journal: Nature Communications

Article Title: Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia

doi: 10.1038/s41467-025-65134-y

Figure Lengend Snippet: a Bar graph of significant gene ontologies based on the top 100 differentially expressed genes in malignant cells of group 2 T-ALL patients compared to group 1 T-ALL patients (Supplementary Data ) as analyzed by DAVID Gene ontology. P -value is derived from a Modified Fisher’s Exact Test. Immunoreg: Immunoregulatory interactions between a lymphoid and non-lymphoid cell. b Ligand-receptor interactions (NATMI ) between NC monocytes and malignant cells from T-ALL group 2 patients. c , d Violin plots showing surface protein expression of CD54 in NC monocytes from healthy donors ( n = 102 cells (BM), n = 168 cells (PB)), T-ALL group 1 ( n = 881 cells (PB), n = 1531 cells (BM)) and T-ALL group 2 ( n = 1603 cells (PB), n = 1226 cells (BM)) at diagnosis ( c ), and CD11a and CD18 in malignant cells from T-ALL group 1 ( n = 4 (BM), n = 6 (PB)) and T-ALL group 2 ( n = 1 (BM), n = 4 (PB)) patients (downsampled to 300 cells/sample) at diagnosis ( d ). A one-way Anova test followed by Tukey’s HSD post-hoc test ( c ) or an unpaired t-test ( d ) was used for statistical analysis. e Viability as assessed by CellTiter-Glo assay upon GGTI-298 treatment in T-ALL cell lines (Jurkat, HPB-ALL and CCRF-CEM) for three days and two primary T-ALL samples from group 2 (P8 and P14) for five days. Viability is normalized to vehicle control DMSO. Each dot represents a data point from an independent replicate. Bars and error bars represent the mean and SEM of triplicates. f Heatmap of normalized cytochrome c - cells upon 12-hour treatment with GGTI-298 or vehicle DMSO in T-ALL cell lines Jurkat, HPB-ALL and CCRF-CEM. g Most synergistic area score (MSA) (Bliss, SynergyFinder ) of combination treatment with Rap1 inhibitor GGTI-298 and indicated drugs in T-ALL cell lines (Jurkat, HPB-ALL and CCRF-CEM) and two primary T-ALL patients samples from group 2. MSA > 10 is considered strongly synergistic (dashed line). Each dot represents the MSA and error bars indicate 95% confidence interval. h Dose-response curves (CellTiter-Glo assay) of T-ALL cell lines (Jurkat and HPB-ALL) and primary T-ALL P14 treated with various concentrations of GGTI-298 and navitoclax (top) or venetoclax (bottom) for three or five days, respectively. Viability of GGTI-298 without addition of BCL2 inhibitors were normalized and set to 100%. Most synergistic area score (MSA) (Bliss, SynergyFinder ) is shown (see ( g )). Each dot represents the mean and error bars represent SEM of three independent replicates.

Article Snippet: Cells were treated for 3 days (T-ALL cell lines) or 5 days (primary T-ALL cells) at indicated concentrations of Rap1 inhibitor GGTI298 (MedChemExpress, HY-15871), navitoclax (MedChemExpress, HY-10087) and venetoclax (MedChemExpress, HY-15531).

Techniques: Derivative Assay, Modification, Expressing, Biomarker Discovery, Glo Assay, Control

Journal: Nature Communications

Article Title: Remodeling of the immune microenvironment is linked to adverse outcome in pediatric T cell acute lymphoblastic leukemia

doi: 10.1038/s41467-025-65134-y

Figure Lengend Snippet: a Heatmap of scaled normalized RNA expression of top 15 genes differentially expressed in leukemia cells of group 1 T-ALL patients and group 2 T-ALL patients. A score for each group was computed based on the sum of expression of these genes. b Violin plots showing surface protein expression of genes present in the T-ALL transcriptomic scores shown in ( a ) for malignant cells from T-ALL group 1 ( n = 4 (BM), n = 6 (PB)) and T-ALL group 2 ( n = 1 (BM), n = 4 (PB)) patients (downsampled to 300 cells/sample) at diagnosis. An unpaired t-test was used for statistical analysis; n.s.: not significant. c Group 2 scores for primary T-ALL patient samples of an independent dataset ( GSE181157 ) split by percentage of CD4 - CD8 - CD7 - T cells analyzed by flow cytometry ( < 3% n = 11, >3% n = 3, see Supplementary Fig. ). A Wilcoxon rank-sum test was used for statistical analysis. d Visualization of T-ALL oncogenic groups ordered by group 2 scores for patient samples from the TARGET cohort ( n = 265). A chi-square test comparing lower tertile and upper tertile was used for statistical analysis. e Kaplan-Meier curve of event-free survival (EFS, n = 580) and overall survival (OS, n = 597) of MRD low T-ALL patients from the Gabriella Miller Kids First Pediatric Research Program dbGaP phs002276.v2.p1 grouped based on score for group 2. A log-rank test was used for statistical analysis to compare high versus low score groups, also see Supplementary Fig. . f Illustration of the remodeled immune system and leukemic Rap1 signaling in group 2 T-ALL patients.

Article Snippet: Cells were treated for 3 days (T-ALL cell lines) or 5 days (primary T-ALL cells) at indicated concentrations of Rap1 inhibitor GGTI298 (MedChemExpress, HY-15871), navitoclax (MedChemExpress, HY-10087) and venetoclax (MedChemExpress, HY-15531).

Techniques: RNA Expression, Expressing, Biomarker Discovery, Flow Cytometry