SYK inhibition sensitizes resistant primary cells to conventional drugs. (a) SYK Y525, measured by RPPA analysis, is upregulated in patients who relapsed (Relapsed, n = 11, median 29,756.5 AU) compared to patients who did not relapse (Not Relapsed, n = 53, median 25,578.5 AU) (unpaired t test with Welch’s correction, p = 0.02). (b) The total form of SYK is not differentially expressed between the two groups of patients (Not Relapsed n = 53, median 22,702 AU; Relapsed n = 11, median 26,511 AU). Results are presented as median ± max to min value. (c) Entospletinib decreases the cell viability of ETV6-RUNX1 primary samples at diagnosis. Annexin V/PI staining of primary cells from ETV6-RUNX1 patients at diagnosis (Not Relapsed n = 12, Relapsed n = 5), treated with VDA (1000 units, corresponding to a cocktail of 1 μM VCR, dex and AraC, respectively) and entospletinib (ento, 100 μM) alone or in combination for 48 h. The percentage of dead cells, defined as the total of Annexin V+/PI−, Annexin V+/PI+ and Annexin V−/PI+, was established after normalizing cells on DMSO-treated cells. Paired t test; * p ≤ 0.05, ** p ≤ 0.01; *** p ≤ 0.001. Results are presented as means ± SEM. (d) Entospletinib decreases the cell viability of ETV6-RUNX1 primary samples at relapse. Annexin V/PI staining of primary cells from ETV6-RUNX1 patients at relapse (n = 5), treated with VDA (1000 units) and entospletinib (ento, 100 μM) alone or in combination for 48 h. The percentage of dead cells, defined as the total of Annexin V+/PI−, Annexin V+/PI+ and Annexin V−/PI+, was established after normalizing cells on DMSO-treated cells. Paired t test; * p ≤ 0.05, ** p ≤ 0.01. Results are presented as means ± SEM.