Skip to main content
letter
. 2024 Feb 29;109(7):2309–2315. doi: 10.3324/haematol.2023.284271

Figure 3.

Figure 3.

Efficacy of DYRK1A inhibition in novel human Down syndrome acute lymphoblastic leukemia cell lines and patient-derived xenograft models. (A) Representative flow plots assessing CD38 and TSLPR expression of the human DS-PER962 and DS-PER961 Down syndrome acute lymphoblastic leukemia (DS-ALL) cell lines compared to their corresponding DS06 and DS02 patient-derived xenografts (PDX), and to NSG recipients engrafted with 1x106 DS-ALL cell lines (PDXcells). (B) Western blots assessing the constitutive phosphorylation of JAK2, STAT5 and ERK1/2 in DS-PER962 and DS-PER961 cell lines following a 6-hour starvation; the non-DS MHH-CALL4 (CRLF2-rearranged/JAK2 mutant) ALL cell line was used as control. (C) Kaplan-Meier curves comparing the survival of the DS-PER962 and DS-PER961 PDX (N=3-4) to their corresponding DS02 and DS06 PDX (N=9-12); ***P<0.001. (D) Efficacy of EHT1610, Leucettinib-21 (LCTB-21) and its inactive isomer iso-Leucettinib-21 (Iso LCTB-21) in the human DS-PER962 and DS-PER961 cell lines (72 hours). (E) Heatmap representing the relative half-maximal inhibitory concentration (IC50) values obtained in the non-DS-ALL, DS-ALL human cell lines and DS-ALL cells freshly harvested from PDX models. (F) Western blot comparing the effect of EHT1610, LCTB-21 and AM30 on phospho-cyclin D3 and total cyclin D3 stability after 6 hours of treatment in the DS-PER962 cell line. (G) ZIP scores obtained from combining Leucettinib-21 (10 doses from 0.01 to 10 μM) with trametinib (0.0001-20 μM), ruxolitinib (0.0001-20 μM), vincristine (0.0005-0.5 μM), dexamethasone (0.00025-20 μM) and L-asparaginase (0.1-20 μM) in the human DS-ALL cell lines. ZIP scores <-10 =antagonism; -10 to 10 =additive; >10 =synergy. (H) In vivo effect of Leucettinib-21 on leukemia burden in the peripheral blood (PB) of the DS02 and DS06 PDX models (oral gavage, 2 weeks and 4 weeks of treatment respectively); *P<0.05, **P<0.01. Veh: vehicle.